Impact of neuroimaging in the pretreatment evaluation of early stage non-small cell lung cancer.

BACKGROUND: There are limited data and conflicting guideline recommendations regarding the role of neuroimaging in the pretreatment evaluation of non-small cell lung cancer (NSCLC). METHODS: We performed a retrospective, pragmatic cohort study of patients with NSCLC diagnosed between January 1 and December 31, 2015. Eligible patients were identified from an institutional tumor registry. We collected all records of pretreatment neuroimaging within 12 weeks of diagnosis, including CT head (CT) and MRI brain (MRI). We abstracted the indication for neuroimaging, presence of central neurologic symptoms and cancer stage (with and without neuroimaging findings) from the tumor registry and the electronic health record. RESULTS: We identified 216 evaluable patients with newly diagnosed NSCLC. 157 of 216 patients (72.7%) underwent neuroimaging as part of initial staging, and 41 (26%) were found to have brain metastases. Of 43 patients with central neurologic symptoms at the time of neuroimaging, 28 (67%) had brain metastasis. In patients without central neurologic symptoms, brain metastases were discovered in 0 of 33 patients with clinical stage I or II, 4 of 36 (11%) with clinical stage III and 9 of 45 (20%) with clinical stage IV disease. CONCLUSIONS: In patients with early stage NSCLC (i.e. clinical stage I and II) without central neurologic symptoms, brain metastases are unlikely. The continued use of neuroimaging in the pretreatment evaluation of clinical stage I patients without central neurologic symptoms is not needed.

Quantitative magnetic susceptibility mapping without phase unwrapping using WASSR.

The magnetic susceptibility of tissue within and around an image voxel affects the magnetic field and thus the local frequency in that voxel. Recently, it has been shown that spatial maps of frequency can be used to quantify local susceptibility if the contributions of surrounding tissue can be deconvolved. Currently, such quantitative susceptibility mapping (QSM) methods employ gradient recalled echo (GRE) imaging to measure spatial differences in the signal phase evolution as a function of echo time, from which frequencies can be deduced. Analysis of these phase images, however, is complicated by phase wraps, despite the availability and usage of various phase unwrapping algorithms. In addition, lengthy high-resolution GRE scanning often heats the magnet bore, causing the magnetic field to drift over several Hertz, which is on the order of the frequency differences between tissues. Here, we explore the feasibility of applying the WAter Saturation Shift Referencing (WASSR) method for 3D whole brain susceptibility imaging. WASSR uses direct saturation of water protons as a function of frequency irradiation offset to generate frequency maps without phase wraps, which can be combined with any image or spectroscopy acquisition. By utilizing a series of fast short-echo-time direct saturation images with multiple radiofrequency offsets, a frequency correction for field drift can be applied based on the individual image phases. Regions of interest were delineated with an automated atlas-based method, and the average magnetic susceptibilities calculated from frequency maps obtained from WASSR correlated well with those from the phase-based multi-echo GRE approach at 3T.

Mapping magnetic susceptibility anisotropies of white matter in vivo in the human brain at 7 T.

High-resolution magnetic resonance phase- or frequency-shift images acquired at high field show contrast related to magnetic susceptibility differences between tissues. Such contrast varies with the orientation of the organ in the field, but the development of quantitative susceptibility mapping (QSM) has made it possible to reproducibly image the intrinsic tissue susceptibility contrast. However, recent studies indicate that magnetic susceptibility is anisotropic in brain white matter and, as such, needs to be described by a symmetric second-rank tensor( ̅χ). To fully determine the elements of this tensor, it would be necessary to acquire frequency data at six or more orientations. Assuming cylindrical symmetry of the susceptibility tensor in myelinated white matter fibers, we propose a simplified method to reconstruct the susceptibility tensor in terms of a mean magnetic susceptibility, MMS=(χ(//)+2 χ(⊥))/3 and a magnetic susceptibility anisotropy, MSA=χ(//)-χ(⊥), where χ(//) and χ(⊥) are susceptibility parallel and perpendicular to the white matter fiber direction, respectively. Computer simulations show that with a practical head rotation angle of around 20°-30°, four head orientations suffice to reproducibly reconstruct the tensor with good accuracy. We tested this approach on whole brain 1 × 1 × 1 mm(3) frequency data acquired from five healthy subjects at 7 T. The frequency information from phase images collected at four head orientations was combined with the fiber direction information extracted from diffusion tensor imaging (DTI) to map the white matter susceptibility tensor. The MMS and MSA were quantified for regions in several large white matter fiber structures, including the corona radiata, posterior thalamic radiation and corpus callosum. MMS ranged from -0.037 to -0.053 ppm (referenced to CSF being about zero). MSA values could be quantified without the need for a reference and ranged between 0.004 and 0.029 ppm, in line with the expectation that the susceptibility perpendicular to the fiber is more diamagnetic than the one parallel to it.

Multi-parametric neuroimaging reproducibility: a 3-T resource study.

Modern MRI image processing methods have yielded quantitative, morphometric, functional, and structural assessments of the human brain. These analyses typically exploit carefully optimized protocols for specific imaging targets. Algorithm investigators have several excellent public data resources to use to test, develop, and optimize their methods. Recently, there has been an increasing focus on combining MRI protocols in multi-parametric studies. Notably, these have included innovative approaches for fusing connectivity inferences with functional and/or anatomical characterizations. Yet, validation of the reproducibility of these interesting and novel methods has been severely hampered by the limited availability of appropriate multi-parametric data. We present an imaging protocol optimized to include state-of-the-art assessment of brain function, structure, micro-architecture, and quantitative parameters within a clinically feasible 60-min protocol on a 3-T MRI scanner. We present scan-rescan reproducibility of these imaging contrasts based on 21 healthy volunteers (11 M/10 F, 22-61 years old). The cortical gray matter, cortical white matter, ventricular cerebrospinal fluid, thalamus, putamen, caudate, cerebellar gray matter, cerebellar white matter, and brainstem were identified with mean volume-wise reproducibility of 3.5%. We tabulate the mean intensity, variability, and reproducibility of each contrast in a region of interest approach, which is essential for prospective study planning and retrospective power analysis considerations. Anatomy was highly consistent on structural acquisition (~1-5% variability), while variation on diffusion and several other quantitative scans was higher (~<10%). Some sequences are particularly variable in specific structures (ASL exhibited variation of 28% in the cerebral white matter) or in thin structures (quantitative T2 varied by up to 73% in the caudate) due, in large part, to variability in automated ROI placement. The richness of the joint distribution of intensities across imaging methods can be best assessed within the context of a particular analysis approach as opposed to a summary table. As such, all imaging data and analysis routines have been made publicly and freely available. This effort provides the neuroimaging community with a resource for optimization of algorithms that exploit the diversity of modern MRI modalities. Additionally, it establishes a baseline for continuing development and optimization of multi-parametric imaging protocols.

q-space and conventional diffusion imaging of axon and myelin damage in the rat spinal cord after axotomy.

Parallel and perpendicular diffusion properties of water in the rat spinal cord were investigated 3 and 30 days after dorsal root axotomy, a specific insult resulting in early axonal degeneration followed by later myelin damage in the dorsal column white matter. Results from q-space analysis (i.e., the diffusion probability density function) obtained with strong diffusion weighting were compared to conventional anisotropy and diffusivity measurements at low b-values, as well as to histology for axon and myelin damage. q-Space contrasts included the height (return to zero displacement probability), full width at half maximum, root mean square displacement, and kurtosis excess of the probability density function, which quantifies the deviation from gaussian diffusion. Following axotomy, a significant increase in perpendicular diffusion (with decreased kurtosis excess) and decrease in parallel diffusion (with increased kurtosis excess) were found in lesions relative to uninjured white matter. Notably, a significant change in abnormal parallel diffusion was detected from 3 to 30 days with full width at half maximum, but not with conventional diffusivity. Also, directional full width at half maximum and root mean square displacement measurements exhibited different sensitivities to white matter damage. When compared to histology, the increase in perpendicular diffusion was not specific to demyelination, whereas combined reduced parallel diffusion and increased perpendicular diffusion was associated with axon damage.

Reproducibility of tract-specific magnetization transfer and diffusion tensor imaging in the cervical spinal cord at 3 tesla.

Damage to specific white matter tracts within the spinal cord can often result in the particular neurological syndromes that characterize myelopathies such as traumatic spinal cord injury. Noninvasive visualization of these tracts with imaging techniques that are sensitive to microstructural integrity is an important clinical goal. Diffusion tensor imaging (DTI)- and magnetization transfer (MT)-derived quantities have shown promise in assessing tissue health in the central nervous system. In this paper, we demonstrate that DTI of the cervical spinal cord can reliably discriminate sensory (dorsal) and motor (lateral) columns. From data derived from nine healthy volunteers, two raters quantified column-specific parallel (lambda(||)) and perpendicular (lambda(perpendicular)) diffusivity, fractional anisotropy (FA), mean diffusivity (MD), and MT-weighted signal intensity relative to cerebrospinal fluid (MTCSF) over two time-points separated by more than 1 week. Cross-sectional means and standard deviations of these measures in the lateral and dorsal columns were as follows: lambda(||): 2.13 +/- 0.14 and 2.14 +/- 0.11 microm(2)/ms; lambda(perpendicular): 0.67 +/- 0.16 and 0.61 +/- 0.09 microm(2)/ms; MD: 1.15 +/- 0.15 and 1.12 +/- 0.08 microm(2)/ms; FA: 0.68 +/- 0.06 and 0.68 +/- 0.05; MTCSF: 0.52 +/- 0.05 and 0.50 +/- 0.05. We examined the variability and interrater and test-retest reliability for each metric. These column-specific MR measurements are expected to enhance understanding of the intimate structure-function relationship in the cervical spinal cord and may be useful for the assessment of disease progression.

Complex geometric models of diffusion and relaxation in healthy and damaged white matter.

Which aspects of tissue microstructure affect diffusion weighted MRI signals? Prior models, many of which use Monte-Carlo simulations, have focused on relatively simple models of the cellular microenvironment and have not considered important anatomic details. With the advent of higher-order analysis models for diffusion imaging, such as high angular resolution diffusion imaging (HARDI), more realistic models are necessary. This paper presents and evaluates the reproducibility of simulations of diffusion in complex geometries. Our framework is quantitative, does not require specialized hardware, is easily implemented with little programming experience, and is freely available as open-source software. Models may include compartments with different diffusivities, permeabilities, and T2 time constants using both parametric (e.g. spheres and cylinders) and arbitrary (e.g. mesh-based) geometries. Three-dimensional diffusion displacement probability functions are mapped with high reproducibility, and thus can be readily used to assess reproducibility of diffusion-derived contrasts.

Diffusion tensor magnetic resonance imaging of Wallerian degeneration in rat spinal cord after dorsal root axotomy.

Diffusion tensor imaging (DTI) and immunohistochemistry were used to examine axon injury in the rat spinal cord after unilateral L(2)-L(4) dorsal root axotomy at multiple time points (from 16 h to 30 d after surgery). Three days after axotomy, DTI revealed a lesion in the ipsilateral dorsal column extending from the lumbar to the cervical cord. The lesion showed significantly reduced parallel diffusivity and increased perpendicular diffusivity at day 3 compared with the contralateral unlesioned dorsal column. These findings coincided with loss of phosphorylated neurofilaments, accumulation of nonphosphorylated neurofilaments, swollen axons and formation of myelin ovoids, and no clear loss of myelin (stained by Luxol fast blue and 2'-3'-cyclic nucleotide 3'-phosphodiesterase). At day 30, DTI of the lesion continued to show significantly decreased parallel diffusivity. There was a slow but significant increase in perpendicular diffusivity between day 3 and day 30, which correlated with gradual clearance of myelin without further significant changes in neurofilament levels. These results show that parallel diffusivity can detect axon degeneration within 3 d after injury. The clearance of myelin at later stages may contribute to the late increase in perpendicular diffusivity, whereas the cause of its early increase at day 3 may be related to changes associated with primary axon injury. These data suggest that there is an early imaging signature associated with axon transections that could be used in a variety of neurological disease processes.

Measurement of T1 and T2 in the cervical spinal cord at 3 tesla.

T(1) and T(2) were measured for white matter (WM) and gray matter (GM) in the human cervical spinal cord at 3T. T(1) values were calculated using an inversion-recovery (IR) and B(1)-corrected double flip angle gradient echo (GRE) and show significant differences (p = 0.002) between WM (IR = 876 +/- 27 ms, GRE = 838 +/- 54 ms) and GM (IR = 973 +/- 33 ms, GRE = 994 +/- 54 ms). IR showed significant difference between lateral and dorsal column WM (863 +/- 23 ms and 899 +/- 18 ms, respectively, p = 0.01) but GRE did not (p = 0.40). There was no significant difference (p = 0.31) in T(2) between WM (73 +/- 6 ms) and GM (76 +/- 3 ms) or between lateral and dorsal columns (lateral: 73 +/- 6 ms, dorsal: 72 +/- 7 ms, p = 0.59). WM relaxation times were similar to brain structures with very dense fiber packing (e.g., corpus callosum), while GM values resembled deep GM in brain. Optimized sequence parameters for maximal contrast between WM and GM, and between WM and cerebrospinal fluid (CSF) were derived. Since the spinal cord has rostral-caudal symmetry, we expect these findings to be applicable to the whole cord.

Diffusion tensor imaging at low SNR: nonmonotonic behaviors of tensor contrasts.

Diffusion tensor imaging (DTI) provides measurements of directional diffusivities and has been widely used to characterize changes in the tissue microarchitecture of the brain. DTI is gaining prominence in applications outside of the brain, where resolution, motion and short T2 values often limit the achievable signal-to-noise ratio (SNR). Consequently, it is important to revisit the topic of tensor estimation in low-SNR regimes. A theoretical framework is developed to model noise in DTI, and by using simulations based on this theory, the degree to which the noise, tensor estimation method and acquisition protocol affect tensor-derived quantities, such as fractional anisotropy and apparent diffusion coefficient, is clarified. These results are then validated against clinical data. It is shown that reliability of tensor contrasts depends on the noise level, estimation method, diffusion-weighting scheme and underlying anatomy. The propensity for bias and errors does not monotonically increase with noise. Comparative results are shown in both graphical and tabular forms, so that decisions about suitable acquisition protocols and processing methods can be made on a case-by-case basis without exhaustive experimentation.

High b-value q-space diffusion-weighted MRI of the human cervical spinal cord in vivo: feasibility and application to multiple sclerosis.

Q-space analysis is an alternative analysis technique for diffusion-weighted imaging (DWI) data in which the probability density function (PDF) for molecular diffusion is estimated without the need to assume a Gaussian shape. Although used in the human brain, q-space DWI has not yet been applied to study the human spinal cord in vivo. Here we demonstrate the feasibility of performing q-space imaging in the cervical spinal cord of eight healthy volunteers and four patients with multiple sclerosis. The PDF was computed and water displacement and zero-displacement probability maps were calculated from the width and height of the PDF, respectively. In the dorsal column white matter, q-space contrasts showed a significant (P < 0.01) increase in the width and a decrease in the height of the PDF in lesions, the result of increased diffusion. These q-space contrasts, which are sensitive to the slow diffusion component, exhibited improved detection of abnormal diffusion compared to perpendicular apparent diffusion constant measurements. The conspicuity of lesions compared favorably with magnetization transfer (MT)-weighted images and quantitative CSF-normalized MT measurements. Thus, q-space DWI can be used to study water diffusion in the human spinal cord in vivo and is well suited to assess white matter damage.

Multiparametric magnetic resonance imaging analysis of the corticospinal tract in multiple sclerosis.

BACKGROUND/PURPOSE: Muscle weakness is an important feature of multiple sclerosis and is responsible for much of the disability associated with that condition. Here, we describe the quantitative magnetic resonance imaging (MRI) attributes of the major intracerebral motor pathway--the corticospinal tract--in multiple sclerosis. To do so, we develop an intuitive method for creating and displaying spatially normalized tract-specific imaging data. METHODS: In 75 individuals with multiple sclerosis and 29 healthy controls, the corticospinal tracts were reconstructed from diffusion tensor imaging at 3 T. Multiple MRI indices--T2 relaxation time; fractional anisotropy; mean, longitudinal, and transverse diffusivity; and magnetization transfer ratio--were examined within the reconstructed tracts. Spatially normalized tract profiles were created to compare, across subjects, the variation in MRI index as a function of tract position. RESULTS: Each index's tract profile had a characteristic shape. Individual subjects had markedly abnormal tract profiles, particularly at lesion sites. On average, tract profiles were different between patients and controls, particularly in the subcortical white matter and corona radiata, for all indices examined except for fractional anisotropy. Magnetization transfer ratio was further decreased in subjects with secondary progressive disease. Tract asymmetry was increased in multiple sclerosis compared to controls. CONCLUSION: Multiparametric MRI allows rapid detection, localization, and characterization of tract-specific abnormalities in multiple sclerosis. Tract profiles bridge the gap between whole-brain imaging of neurological disease and the interrogation of individual, functionally relevant subsystems.

Effects of signal-to-noise ratio on the accuracy and reproducibility of diffusion tensor imaging-derived fractional anisotropy, mean diffusivity, and principal eigenvector measurements at 1.5 T.

PURPOSE: To develop an experimental protocol to calculate the precision and accuracy of fractional anisotropy (FA), mean diffusivity (MD), and the orientation of the principal eigenvector (PEV) as a function of the signal-to-noise ratio (SNR) in vivo. MATERIALS AND METHODS: A healthy male volunteer was scanned in three separate scanning sessions, yielding a total of 45 diffusion tensor imaging (DTI) scans. To provide FA, MD, and PEV as a function of SNR, sequential scans from a scan session were grouped into nonintersecting sets. Analysis of the accuracy and precision of the DTI-derived contrasts was done in both a voxel-wise and region of interest (ROI)-based manner. RESULTS: An upward bias of FA and no significant bias in MD were present as SNR decreased, confirming results from simulation-based studies. Notably, while the precision of the PEV became worse at low SNR, no bias in the PEV orientation was observed. Overall, an accurate and precise quantification of FA values in GM requires substantially more SNR than the quantification of white matter (WM) FA values CONCLUSION: This study provides guidance for FA, MD, and PEV quantification and a means to investigate the minimal detectable differences within and across scan sessions as a function of SNR.

Effects of diffusion weighting schemes on the reproducibility of DTI-derived fractional anisotropy, mean diffusivity, and principal eigenvector measurements at 1.5T.

Diffusion tensor imaging (DTI) is used to study tissue composition and architecture in vivo. To increase the signal to noise ratio (SNR) of DTI contrasts, studies typically use more than the minimum of 6 diffusion weighting (DW) directions or acquire repeated observations of the same set of DW directions. Simulation-based studies have sought to optimize DTI acquisitions and suggest that increasing the directional resolution of a DTI dataset (i.e., the number of distinct directions) is preferable to repeating observations, in an equal scan time comparison. However, it is not always clear how to translate these recommendations into practice when considering physiological noise and scanner stability. Furthermore, the effect of different DW schemes on in vivo DTI findings is not fully understood. This study characterizes how the makeup of a DW scheme, in terms of the number of directions, impacts the precision and accuracy of in vivo fractional anisotropy (FA), mean diffusivity (MD), and principal eigenvector (PEV) findings. Orientation dependence of DTI reliability is demonstrated in vivo and a principled theoretical framework is provided to support and interpret findings with simulation results. As long as sampling orientations are well balanced, differences in DTI contrasts due to different DW schemes are shown to be small relative to intra-session variability. These differences are accentuated at low SNR, while minimized at high SNR. This result suggests that typical clinical studies, which use similar protocols but different well-balanced DW schemes, are readily comparable within the experimental precision.

Pulsed magnetization transfer imaging with body coil transmission at 3 Tesla: feasibility and application.

Pulsed magnetization transfer (MT) imaging has been applied to quantitatively assess brain pathology in several diseases, especially multiple sclerosis (MS). To date, however, because of the high power deposition associated with the use of short, rapidly repeating MT prepulses, clinical application has been limited to lower field strengths. The contrast-to-noise ratio (CNR) of MT is limited, and this method would greatly benefit from the use of higher magnetic fields and phased-array coil reception. However, power deposition is proportional to the square of the magnetic field and scales with coil size, and MT experiments are already close to the SAR limit at 1.5T even when smaller transmit coils are used instead of the body coil. Here we show that these seemingly great obstacles can be ameliorated by the increased T(1) of tissue water at higher field, which allows for longer maintenance of sufficiently high saturation levels while using a reduced duty cycle. This enables a fast (5-6 min) high-resolution (1.5 mm isotropic) whole-brain MT acquisition with excellent anatomical visualization of gray matter (GM) and white matter (WM) structures, and even substructures. The method is demonstrated in nine normal volunteers and five patients with relapsing remitting MS (RRMS), and the results show a clear delineation of heterogeneous lesions.