Roland G. Henry

Diffusion Tensor MR Imaging and Fiber Tractography: Theoretic Underpinnings

SUMMARY: In this article, the underlying theory of clinical diffusion MR imaging, including diffusion tensor imaging (DTI) and fiber tractography, is reviewed. First, a brief explanation of the basic physics of diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) mapping is provided. This is followed by an overview of the additional information that can be derived from the diffusion tensor, including diffusion anisotropy, color-encoded fiber orientation maps, and 3D fiber tractography. This article provides the requisite background for the second article in this 2-part review to appear next month, which covers the major technical factors that affect image quality in diffusion MR imaging, including the acquisition sequence, magnet field strength, gradient amplitude and slew rate, and multichannel radio-frequency coils and parallel imaging. The emphasis is on optimizing these factors for state-of-the-art DWI and DTI based on the best available evidence in the literature.

Diffusion tensor imaging: serial quantitation of white matter tract maturity in premature newborns.

Magnetic resonance diffusion tensor imaging (DTI) enables the discrimination of white matter pathways before myelination is evident histologically or on conventional MRI. In this investigation, 14 premature neonates with no evidence of white matter abnormalities by conventional MRI were studied with DTI. A custom MR-compatible incubator with a novel high sensitivity neonatal head coil and improved acquisition and processing techniques were employed to increase image quality and spatial resolution. The technical improvements enabled tract-specific quantitative characterization of maturing white matter, including several association tracts and subcortical projection tracts not previously investigated in neonates by MR. Significant differences were identified between white matter pathways, with earlier maturing commissural tracts of the corpus callosum, and deep projection tracts of the cerebral peduncle and internal capsule exhibiting lower mean diffusivity (Dav) and higher fractional anisotropy (FA) than later maturing subcortical projection and association pathways. Maturational changes in white matter tracts included reductions in Dav and increases in FA with age due primarily to decreases in the two minor diffusion eigenvalues (lambda2 and lambda3). This work contributes to the understanding of normal white matter development in the preterm neonatal brain, an important step toward the use of DTI for the improved evaluation and treatment of white matter injury of prematurity.

Serial quantitative diffusion tensor MRI of the premature brain: development in newborns with and without injury.

To determine the change over time of the apparent diffusion coefficient (ADC) and relative anisotropy of cerebral water in a cohort of premature newborns serially studied near birth and again near term.

Diffusion tensor MR imaging and fiber tractography: technical considerations.

SUMMARY:This second article of the 2-part review builds on the theoretic background provided by the first article to cover the major technical factors that affect image quality in diffusion imaging, including the acquisition sequence, magnet field strength, gradient amplitude, and slew rate as well as multichannel radio-frequency coils and parallel imaging. The sources of many common diffusion image artifacts are also explored in detail. The emphasis is on optimizing these technical factors for state-of-the-art diffusion-weighted imaging and diffusion tensor imaging (DTI) based on the best available evidence in the literature. An overview of current methods for quantitative analysis of DTI data and fiber tractography in clinical research is also provided.

A voxel-based morphometry study of patterns of brain atrophy in ALS and ALS/FTLD

Objective: To investigate the patterns of MRI brain atrophy in patients with ALS with and without clinically evident frontotemporal lobar dementia (FTLD) using voxel-based morphometry (VBM). Methods: Voxel-based morphometry was used to compare T1-weighted MRI images obtained from ten ALS patients with FTLD, ten ALS patients who were cognitively and behaviorally normal, and 22 control subjects. Images from patients and controls were spatially pre-processed using a study-specific, customized template and a priori images. A statistical threshold of p < 0.05 corrected for multiple comparisons determined significance. Results: A common pattern of gray matter atrophy was seen in both ALS and ALS/FTLD patients when compared to controls that involved the bilateral motor/premotor cortices, the left middle and inferior frontal gyri, the anterior portion of the superior frontal gyri, the superior temporal gyri, the temporal poles and left posterior thalamus. Most of the frontal regions were significantly more atrophied in the ALS/FTLD group than in the ALS group. No significant differences were found in white matter volumes. Conclusions: Patients with ALS and ALS associated with frontotemporal lobar degeneration exhibit widespread gray matter atrophy in frontotemporal regions. This finding supports the idea of a clinical and anatomic continuum between ALS and frontotemporal lobar degeneration.

Quantitative diffusion tensor MRI fiber tractography of sensorimotor white matter development in premature infants.

Diffusion tensor MRI (DTI) fiber tracking is the first non-invasive and in vivo technique for the delineation and quantitation of specific white matter pathways. In this study, quantitative fiber tracking was used to assess the structural development of the motor tract and somatosensory radiation in premature human newborns. These pathways are unmyelinated in the youngest premature infants and begin to myelinate during late preterm maturation. Previous studies have only been able to delineate parts of these pathways that could be manually outlined in 2D based on anatomical landmarks. Furthermore, these previous studies could not separate motor and sensory regions. A high-sensitivity neonatal head coil was employed in conjunction with an MR-compatible incubator to perform high-resolution imaging of the premature infant brain. The motor and somatosensory tracts were successfully delineated with 3D DTI fiber tracking in 37 exams of preterm newborns between 28 and 43 weeks gestational age. Both streamline deterministic and probabilistic methods were employed to perform quantitative fiber tractography. Tract-specific measurements of diffusion parameters including fractional anisotropy, directionally averaged diffusivity, and eigenvalues were obtained from the motor and sensory pathways. Using both deterministic and probabilistic fiber tracking, all tract-specific diffusion parameters were found to be significantly correlated with age and the motor tracts were found to have higher anisotropy and lower diffusivity than the sensory pathway. By segmenting the 3D fiber tracks by slice, measurements from different axial levels of the brain were found to vary with region and age. In summary, deterministic and probabilistic DTI fiber tracking methods were used to quantify the developmental changes of motor and somatosensory pathways in premature infants.

Neural Stem Cell Engraftment and Myelination in the Human Brain

Neural stem cell transplantation study suggests myelin formation in children with a severe hypomyelination disorder. Bringing Insulation Up to Code Faulty insulation around household wiring is an electric shock and fire hazard; likewise, defects in the insulation around nerve fibers—the myelin sheath—can have destructive effects. Because of myelin’s crucial roles in promoting the rapid transmission of nerve impulses and in axon integrity, mutations that affect myelin formation in the central nervous system cause severe neurological decline. Uchida et al. and Gupta et al. now investigate the use of neural stem cells—which can differentiate into myelin-producing oligodendrocytes—as a potential treatment for such disorders. Previous work showed that transplantation of human oligodendrocyte progenitors into newborn shiverer (Shi) mice, a hypomyelination model, could prolong survival. In the new work, Uchida et al. transplanted human neural stem cells, which had been expanded and banked, into the brains of newborn and juvenile Shi mice. Whereas the newborn mice were asymptomatic, the juvenile mice were already symptomatic and displayed advanced dysmyelination. These transplanted cells preferentially differentiated into oligodendrocytes that generated myelin, which ensheathed axons and improved nerve conduction in both categories of mice. In an open-label phase 1 study, Gupta et al. then tested the safety and efficacy of such cells in four young boys with a severe, fatal form of Pelizaeus-Merzbacher disease (PMD), a rare X-linked condition in which oligodendrocytes cannot myelinate axons. Human neural stem cells were transplanted directly into the brain; the procedure and transplantation were well tolerated. Magnetic resonance imaging techniques, performed before transplant and five times in the following year, were used to assess myelination. The imaging results were consistent with donor cell–derived myelination in the transplantation region in three of the four patients. These results support further study of potential clinical benefits of neural stem cell transplantation in PMD and other dysmyelination disorders. Pelizaeus-Merzbacher disease (PMD) is a rare leukodystrophy caused by mutation of the proteolipid protein 1 gene. Defective oligodendrocytes in PMD fail to myelinate axons, causing global neurological dysfunction. Human central nervous system stem cells (HuCNS-SCs) can develop into oligodendrocytes and confer structurally normal myelin when transplanted into a hypomyelinating mouse model. A 1-year, open-label phase-1 study was undertaken to evaluate safety and to detect evidence of myelin formation after HuCNS-SC transplantation. Allogeneic HuCNS-SCs were surgically implanted into the frontal lobe white matter in four male subjects with an early-onset severe form of PMD. Immunosuppression was administered for 9 months. Serial neurological evaluations, developmental assessments, and cranial magnetic resonance imaging (MRI) and MR spectroscopy, including high-angular resolution diffusion tensor imaging (DTI), were performed at baseline and after transplantation. The neurosurgical procedure, immunosuppression regimen, and HuCNS-SC transplantation were well tolerated. Modest gains in neurological function were observed in three of the four subjects. No clinical or radiological adverse effects were directly attributed to the donor cells. Reduced T1 and T2 relaxation times were observed in the regions of transplantation 9 months after the procedure in the three subjects. Normalized DTI showed increasing fractional anisotropy and reduced radial diffusivity, consistent with myelination, in the region of transplantation compared to control white matter regions remote to the transplant sites. These phase 1 findings indicate a favorable safety profile for HuCNS-SCs in subjects with PMD. The MRI results suggest durable cell engraftment and donor-derived myelin in the transplanted host white matter.

Regional grey matter atrophy in clinically isolated syndromes at presentation

Background: The presence and degree of neuronal degeneration already existing in patients at their initial presentation with a clinically isolated syndrome suggestive of multiple sclerosis (CIS) is unclear, and whole brain or whole normalised grey matter analyses have not demonstrated significant atrophy in CIS cohorts at clinical presentation. Voxel-based analyses allow detection of regional atrophy throughout the brain and, therefore, may be sensitive to regional atrophy in CIS patients, and these changes may correspond with clinical disability. Methods: This study used a modified voxel-based morphometry (VBM) method to correct for lesion effects to analyse regional atrophy and perform voxel-wise correlations between volume and clinical metrics in 41 untreated CIS patients at presentation compared with 49 healthy controls. Results: The results confirmed that there was no significant difference in whole normalised grey matter volume between CIS and controls, whereas VBM showed significant areas of bilateral thalamic, hypothalamic, putamen and caudate atrophy. Voxel-wise correlations with clinical measures showed that cerebellar volumes correlated with clinical cerebellar function, nine-hole peg test scores and the Multiple Sclerosis Functional Composite (MSFC) score, and that the MSFC score was also correlated with putamen volume. Lastly, T1 lesion volumes were found to correlate with thalamic and hippocampal atrophy, suggesting a link between white matter lesions and grey matter degeneration at the earliest stages of multiple sclerosis. Conclusions: Atrophy is present in CIS patients at presentations, particularly in the thalamus, and other deep grey matter structures. Furthermore, the correlations with clinical metrics suggest the importance of this atrophy to clinical status and the correlation with T1 lesion load suggests a possible role of Wallerian degeneration.

Accuracy of diffusion tensor magnetic resonance imaging tractography assessed using intraoperative subcortical stimulation mapping and magnetic source imaging

OBJECT Resecting brain tumors involves the risk of damaging the descending motor pathway. Diffusion tensor (DT)-imaged fiber tracking is a noninvasive magnetic resonance (MR) technique that can delineate the subcortical course of the motor pathway. The goal of this study was to use intraoperative subcortical stimulation mapping of the motor tract and magnetic source imaging to validate the utility of DT-imaged fiber tracking as a tool for presurgical planning. METHODS Diffusion tensor-imaged fiber tracks of the motor tract were generated preoperatively in nine patients with gliomas. A mask of the resultant fiber tracks was overlaid on high-resolution T1- and T2-weighted anatomical MR images and used for stereotactic surgical navigation. Magnetic source imaging was performed in seven of the patients to identify functional somatosensory cortices. During resection, subcortical stimulation mapping of the motor pathway was performed within the white matter using a bipolar electrode. RESULTS A total of 16 subcortical motor stimulations were stereotactically identified in nine patients. The mean distance between the stimulation sites and the DT-imaged fiber tracks was 8.7 +/- 3.1 mm (+/- standard deviation). The measured distance between subcortical stimulation sites and DT-imaged fiber tracks combines tracking technique errors and all errors encountered with stereotactic navigation. CONCLUSIONS Fiber tracks delineated using DT imaging can be used to identify the motor tract in deep white matter and define a safety margin around the tract.

Survival analysis in patients with glioblastoma multiforme: Predictive value of choline-to-n-acetylaspartate index, apparent diffusion coefficient, and relative cerebral blood volume

To investigate the potential value of pre‐external‐beam radiation therapy (XRT) choline‐to‐NAA (N‐acetylaspartate) index (CNI), apparent diffusion coefficient (ADC), and relative cerebral blood volume (rCBV) for predicting survival in newly diagnosed patients with glioblastoma multiforme (GBM).