MR spectroscopy quantitation: a review of frequency domain methods.

There has been a vast increase in applications of magnetic resonance spectroscopy (MRS) in biomedical research during the last few years. This is not surprising since MRS provides both in vivo and in vitro a non-invasive tool for various biochemical and biomedical studies. There are also expectations that clinical MRS will have an important role as a diagnostic tool. An essential prerequisite for the future success of MRS for applicability in biomedical sciences will be accurate and biochemically relevant data analysis (at as high a level of automation as possible). This review briefly describes principles of the methodology available for advanced quantitative data analysis in the frequency domain. Various biomedical applications are discussed in order to illustrate the practical aspects of the analyses and to show the applicability and power of biochemical prior knowledge-based lineshape fitting analysis.     

Spatial frequency domain tomography of protoporphyrin IX fluorescence in preclinical glioma models

Multifrequency (0 to 0.3 mm(-1)), multiwavelength (633, 680, 720, 800, and 820 nm) spatial frequency domain imaging (SFDI) of 5-aminolevulinic acid-induced protoporphyrin IX (PpIX) was used to recover absorption, scattering, and fluorescence properties of glioblastoma multiforme spheroids in tissue-simulating phantoms and in vivo in a mouse model. Three-dimensional tomographic reconstructions of the frequency-dependent remitted light localized the depths of the spheroids within 500 μm, and the total amount of PpIX in the reconstructed images was constant to within 30% when spheroid depth was varied. In vivo tumor-to-normal contrast was greater than ～1.5 in reduced scattering coefficient for all wavelengths and was ～1.3 for the tissue concentration of deoxyhemoglobin (ctHb). The study demonstrates the feasibility of SFDI for providing enhanced image guidance during surgical resection of brain tumors.     

Spatial frequency domain imaging of intrinsic optical property contrast in a mouse model of Alzheimer's disease

Extensive changes in neural tissue structure and function accompanying Alzheimer’s disease (AD) suggest that intrinsic signal optical imaging can provide new contrast mechanisms and insight for assessing AD appearance and progression. In this work, we report the development of a wide-field spatial frequency domain imaging (SFDI) method for non-contact, quantitative in vivo optical imaging of brain tissue composition and function in a triple transgenic mouse AD model (3xTg). SFDI was used to generate optical absorption and scattering maps at up to 17 wavelengths from 650 to 970 nm in 20-month-old 3xTg mice (n = 4) and age-matched controls (n = 6). Wavelength-dependent optical properties were used to form images of tissue hemoglobin (oxy-, deoxy-, and total), oxygen saturation, and water. Significant baseline contrast was observed with 13–26% higher average scattering values and elevated water content (52 ± 2% vs. 31 ± 1%); reduced total tissue hemoglobin content (127 ± 9 μM vs. 174 ± 6 μM); and lower tissue oxygen saturation (57 ± 2% vs. 69 ± 3%) in AD vs. control mice. Oxygen inhalation challenges (100% oxygen) resulted in increased levels of tissue oxy-hemoglobin (ctO₂Hb) and commensurate reductions in deoxy-hemoglobin (ctHHb), with ~60–70% slower response times and ~7 μM vs. ~14 μM overall changes for 3xTg vs. controls, respectively. Our results show that SFDI is capable of revealing quantitative functional contrast in an AD model and may be a useful method for studying dynamic alterations in AD neural tissue composition and physiology.     

THz time domain spectroscopy of biomolecular conformational modes

We discuss the use of terahertz time domain spectroscopy for studies of conformational flexibility and conformational change in biomolecules. Protein structural dynamics are vital to biological function with protein flexibility affecting enzymatic reaction rates and sensory transduction cycling times. Conformational mode dynamics occur on the picosecond timescale and with the collective vibrational modes associated with these large scale structural motions in the 1-100 cm(-1) range. We have performed THz time domain spectroscopy (TTDS) of several biomolecular systems to explore the sensitivity of TTDS to distinguish different molecular species, different mutations within a single species and different conformations of a given biomolecule. We compare the measured absorbances to normal mode calculations and find that the TTDS absorbance reflects the density of normal modes determined by molecular mechanics calculations, and is sensitive to both conformation and mutation. These early studies demonstrate some of the advantages and limitations of using TTDS for the study of biomolecules.     

Spatial localization in nuclear magnetic resonance spectroscopy

The ability to select a discrete region within the body for signal acquisition is a fundamental requirement of in vivo NMR spectroscopy. Ideally, it should be possible to tailor the selected volume to coincide exactly with the lesion or tissue of interest, without loss of signal from within this volume or contamination with extraneous signals. Many techniques have been developed over the past 25 years employing a combination of RF coil properties, static magnetic field gradients and pulse sequence design in an attempt to meet these goals. This review presents a comprehensive survey of these techniques, their various advantages and disadvantages, and implications for clinical applications. Particular emphasis is placed on the reliability of the techniques in terms of signal loss, contamination and the effect of nuclear relaxation and J-coupling. The survey includes techniques based on RF coil and pulse design alone, those using static magnetic field gradients, and magnetic resonance spectroscopic imaging. Although there is an emphasis on techniques currently in widespread use (PRESS, STEAM, ISIS and MRSI), the review also includes earlier techniques, in order to provide historical context, and techniques that are promising for future use in clinical and biomedical applications.     

Quantification of prostate MRSI data by model-based time domain fitting and frequency domain analysis

This paper compares two spectral processing methods for obtaining quantitative measures from in vivo prostate spectra, evaluates their effectiveness, and discusses the necessary modifications for accurate results. A frequency domain analysis (FDA) method based on peak integration was compared with a time domain fitting (TDF) method, a model-based nonlinear least squares fitting algorithm. The accuracy of both methods at estimating the choline + creatine + polyamines to citrate ratio (CCP:C) was tested using Monte Carlo simulations, empirical phantom MRSI data and in vivo MRSI data. The paper discusses the different approaches employed to achieve the quantification of the overlapping choline, creatine and polyamine resonances. Monte Carlo simulations showed induced biases on the estimated CCP:C ratios. Both methods were successful in identifying tumor tissue, provided that the CCP:C ratio was greater than a given (normal) threshold. Both methods predicted the same voxel condition in 94% of the in vivo voxels (68 out of 72). Both TDF and FDA methods had the ability to identify malignant voxels in an artifact-free case study using the estimated CCP:C ratio. Comparing the ratios estimated by the TDF and the FDA, the methods predicted the same spectrum type in 17 out of 18 voxels of the in vivo case study (94.4%).     

基于频域信息的意识任务分类

研究了频谱信息在意识任务分类中的应用.用傅里叶变换(FFT)和Burg方法来估计频谱信息,并对比了频谱信息和自回归模型系数在相同特征个数条件下对意识任务分类的作用.结果 显示:①两种频谱估计方法取得了几乎相同的分类结果,频谱信息能提供更高的分类精度;②丢失高频信息会降低分类的效果;③对于较多特征个数的分类需要足够多的训练样本.FFT算法具有简单,速度快的特点,且使用多个特征量并不增加其计算量,这些优点使得傅里叶变换更适合于在线系统的应用与分析.     

Imaging scattering orientation with spatial frequency domain imaging

Optical imaging techniques based on multiple light scattering generally have poor sensitivity to the orientation and direction of microscopic light scattering structures. In order to address this limitation, we introduce a spatial frequency domain method for imaging contrast from oriented scattering structures by measuring the angular-dependence of structured light reflectance. The measurement is made by projecting sinusoidal patterns of light intensity on a sample, and measuring the degree to which the patterns are blurred as a function of the projection angle. We derive a spatial Fourier domain solution to an anisotropic diffusion model. This solution predicts the effects of bulk scattering orientation on the amplitude and phase of the projected patterns. We introduce a new contrast function based on a scattering orientation index (SOI) which is sensitive to the degree to which light scattering is directionally dependent. We validate the technique using tissue simulating phantoms, and ex vivo samples of muscle and brain. Our results show that SOI is independent of the overall amount of bulk light scattering and absorption, and that isotropic versus oriented scattering structures can be clearly distinguished. We determine the orientation of subsurface microscopic scattering structures located up to 600 μm beneath highly scattering (μ(') (s) = 1.5 mm(-1)) material.     

Radiative transport in fluorescence-enhanced frequency domain photon migration

Small animal optical tomography has significant, but potential application for streamlining drug discovery and pre-clinical investigation of drug candidates. However, accurate modeling of photon propagation in small animal volumes is critical to quantitatively obtain accurate tomographic images. Herein we present solutions from a robust fluorescence-enhanced, frequency domain radiative transport equation (RTE) solver with unique attributes that facilitate its deployment within tomographic algorithms. Specifically, the coupled equations describing time-dependent excitation and emission light transport are solved using discrete ordinates (SN) angular differencing along with linear discontinuous finite-element spatial differencing on unstructured tetrahedral grids. Source iteration in conjunction with diffusion synthetic acceleration is used to iteratively solve the resulting system of equations. This RTE solver can accurately and efficiently predict ballistic as well as diffusion limited transport regimes which could simultaneously exist in small animals. Furthermore, the solver provides accurate solutions on unstructured, tetrahedral grids with relatively large element sizes as compared to commonly employed solvers that use step differencing. The predictions of the solver are validated by a series of frequency-domain, phantom measurements with optical properties ranging from diffusion limited to transport limited propagation. Our results demonstrate that the RTE solution consistently matches measurements made under both diffusion and transport-limited conditions. This work demonstrates the use of an appropriate RTE solver for deployment in small animal optical tomography.     

The frequency domain versus time domain methods for processing of intracranial pressure (ICP) signals

Two methods for analyzing intracranial pressure (ICP) waveforms were compared. The frequency domain (FD) method converts the signal from the time domain to the frequency domain by a fast Fourier transform (FFT), while the time domain (TD) method calculates peak-to-peak value of the pulse waveform directly from the time samples. First, the ICP signal was regenerated from the first harmonic of the FFT and compared against the time domain raw ICP signal. We found that the FD method may underestimate pulse amplitude if there is heart rate variability or a high harmonic distortion. Second, to explore the significance in a larger data set, differences between FD- and TD-derived pulse amplitudes were determined for a total of 50,978 6-s time windows of 79 head injury patients. The mean difference in pulse pressure amplitude was 2.9 mmHg for the 50,978 6-s time windows. Differences between TD- and FD-derived pulse amplitudes were >or= 2.0 mmHg in 58.8% of the 50,978 time windows. In about 33% of time windows FD amplitudes were <2 mmHg when TD amplitudes were >or= 4 mmHg, and vice versa. Hence, the TD method is superior to the FD method for calculation of pulse amplitudes. Nevertheless, in this material both the TD and FD methods revealed significantly elevated pulse amplitudes in head injury patients with bad outcome (i.e. Glasgow Outcome Score 1-3).     

Accuracy of subspace mapping of spatiotemporal frequency domain visual receptive fields

Orientation and spatial frequency selectivities are fundamental properties of cells in the early visual cortex. Although they are customarily tested with drifting sinusoidal gratings, a recently developed subspace reverse correlation method may be a better replacement for obtaining a selectivity map in a joint orientation and spatial frequency domain at higher resolution efficiently. These two methods are examined for their accuracy and data compatibility for cells in areas 17 and 18 of anesthetized and paralyzed cats. Peaks and bandwidths of tuning curves from these two methods are highly correlated. However, spatial frequency bandwidths obtained by reverse correlation tend to be slightly narrower for the subspace reverse correlation than those from the drifting grating tests. Consistency between the two methods is improved if the entire duration of data containing signal are taken into account for the subspace reverse correlation rather than using the map only at the optimal correlation delay. Examination of convergence of the subspace mapping process shows that reliable 2-day profiles can be obtained within 5-10 min. for the majority of cells. Temporal dynamics of tuning properties are also examined more directly with the subspace mapping than with the drifting gratings. For many cells, the optimal spatial frequency shifts substantially, measured as a fraction of tuning bandwidth, over the time course of response. In comparison, the optimal orientation remains highly stable throughout the duration of response. Overall, these results suggest that the subspace reverse correlation is a better substitute for the conventional method.     

Spatial sensitivity of acousto-optic and optical near-infrared spectroscopy sensing measurements

Near-infrared spectroscopy (NIRS) is a popular sensing technique to measure tissue oxygenation noninvasively. However, the region of interest (ROI) is often beneath a superficial layer, which affects its accuracy. By applying focused ultrasound in the ROI, acousto-optic (AO) techniques can potentially minimize the effect of physiological changes in the superficial layer. Using absorption perturbation experiments in both transmission and reflection modes, we investigated the spatial sensitivity distributions and mean penetration depths of an AO system based on a digital correlator and two popular NIRS systems based on i. intensity measurements using a single source and detector configuration, and ii. spatially resolved spectroscopy. Our results show that for both transmission and reflection modes, the peak relative sensitivities of the two NIRS systems are near to the superficial regions, whereas those of the AO technique are near to the ROIs. In the reflection mode, when the ROI is deeper than 14 mm, the AO technique has a higher absolute mean sensitivity than the two NIRS techniques. As the focused ultrasound is moved deeper into the turbid medium, the mean penetration depth increases accordingly. The focused ultrasound can shift the peak relative sensitivity of the AO measurement toward its focused region.     

First-in-human pilot study of a spatial frequency domain oxygenation imaging system

Oxygenation measurements are widely used in patient care. However, most clinically available instruments currently consist of contact probes that only provide global monitoring of the patient (e.g., pulse oximetry probes) or local monitoring of small areas (e.g., spectroscopy-based probes). Visualization of oxygenation over large areas of tissue, without a priori knowledge of the location of defects, has the potential to improve patient management in many surgical and critical care applications. In this study, we present a clinically compatible multispectral spatial frequency domain imaging (SFDI) system optimized for surgical oxygenation imaging. This system was used to image tissue oxygenation over a large area (16×12 cm) and was validated during preclinical studies by comparing results obtained with an FDA-approved clinical oxygenation probe. Skin flap, bowel, and liver vascular occlusion experiments were performed on Yorkshire pigs and demonstrated that over the course of the experiment, relative changes in oxygen saturation measured using SFDI had an accuracy within 10% of those made using the FDA-approved device. Finally, the new SFDI system was translated to the clinic in a first-in-human pilot study that imaged skin flap oxygenation during reconstructive breast surgery. Overall, this study lays the foundation for clinical translation of endogenous contrast imaging using SFDI.     

Effects of motion on optical properties in the spatial frequency domain

Spatial frequency domain imaging (SFDI) is a noncontact and wide-field optical imaging technology currently being used to study the optical properties and chromophore concentrations of in vivo skin including skin lesions of various types. Part of the challenge of developing a clinically deployable SFDI system is related to the development of effective motion compensation strategies, which in turn, is critical for recording high fidelity optical properties. Here we present a two-part strategy for SFDI motion correction. After verifying the effectiveness of the motion correction algorithm on tissue-simulating phantoms, a set of skin-imaging data was collected in order to test the performance of the correction technique under real clinical conditions. Optical properties were obtained with and without the use of the motion correction technique. The results indicate that the algorithm presented here can be used to render optical properties in moving skin surfaces with fidelities within 1.5% of an ideal stationary case and with up to 92.63% less variance. Systematic characterization of the impact of motion variables on clinical SFDI measurements reveals that until SFDI instrumentation is developed to the point of instantaneous imaging, motion compensation is necessary for the accurate localization and quantification of heterogeneities in a clinical setting.     

Simulation of ultrasound two-dimensional array transducers using a frequency domain model

Ultrasound imaging with two-dimensional (2D) arrays has garnered broad interest from scanner manufacturers and researchers for real time three-dimensional (3D) applications. Previously the authors described a frequency domain B-mode imaging model applicable for linear and phased array transducers. In this paper, the authors extend this model to incorporate 2D array transducers. Further approximations can be made based on the fact that the dimensions of the 2D array element are small. The model is compared with the widely used ultrasound simulation program FIELD II, which utilizes an approximate form of the time domain impulse response function. In a typical application, errors in simulated RF waveforms are less than 4% regardless of the steering angle for distances greater than 2 cm, yet computation times are on the order of 1/35 of those incurred using FIELD II. The 2D model takes into account the effects of frequency-dependent attenuation, backscattering, and dispersion. Modern beam-forming techniques such as apodization, dynamic aperture, dynamic receive focusing, and 3D beam steering can also be simulated.