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BACKGROUND 3D brain proton MR spectroscopic imaging (1 H MRSI) facilitates simultaneous metabolic profiling of multiple loci, at higher, sub-1 cm3 , spatial resolution than single-voxel 1 H MRS with the ability to separate tissue-type partial volume contribution(s). PURPOSE To determine if: 1) white matter (WM) damage in mild traumatic brain injury (mTBI) is homogeneously diffuse, or if specific regions are more affected; 2) partial-volume-corrected, structure-specific 1 H MRSI voxel averaging is sensitive to regional WM metabolic abnormalities. STUDY TYPE Retrospective cross-sectional cohort study. POPULATION Twenty-seven subjects: 15 symptomatic mTBI patients, 12 matched controls. FIELD STRENGTH/SEQUENCE 3T using 3D 1 H MRSI over a 360-cm3 volume of interest (VOI) centered over the corpus callosum, partitioned into 480 voxels, each 0.75 cm3 . ASSESSMENT N-acetyl-aspartate (NAA), creatine, choline, and myo-inositol concentrations estimated in predominantly WM regions: body, genu, and splenium of the corpus callosum, corona radiata, frontal, and occipital WM. STATISTICAL TESTS Analysis of covariance (ANCOVA) to compare patients with controls in terms of regional concentrations. The effect sizes (Cohen's d) of the mean differences were compared across regions and with previously published global data obtained with linear regression of the WM over the entire VOI in the same dataset. RESULTS Despite patients' global VOI WM NAA being significantly lower than the controls', no regional differences were observed for any metabolite. Regional NAA comparisons, however, were all unidirectional (patients' NAA concentrations < controls') within a narrow range: 0.3 ≤ Cohen's d ≤ 0.6. DATA CONCLUSION Since the patient group was symptomatic and exhibiting global WM NAA deficits, these findings suggest: 1) diffuse axonal mTBI damage; that is 2) below the 1 H MRSI detection threshold in small regions. Therefore, larger, ie, more sensitive, single-voxel 1 H MRS, placed anywhere in WM regions, may be well suited for mTBI 1 H MRS studies, given that these results are confirmed in other cohorts. LEVEL OF EVIDENCE 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:1424-1432.

(1)H-MRSI is commonly performed with gradient phase encoding, due to its simplicity and minimal radio frequency (RF) heating (specific absorption rate). Its two well-known main problems—(i) “voxel bleed” due to the intrinsic point-spread function, and (ii) chemical shift displacement error (CSDE) when slice-selective RF pulses are used, which worsens with increasing volume of interest (VOI) size—have long become accepted as unavoidable. Both problems can be mitigated with Hadamard multislice RF encoding. This is demonstrated and quantified with numerical simulations, in a multislice phantom and in five healthy young adult volunteers at 3 T, targeting a 2-cm thick temporal lobe VOI through the bilateral hippocampus. This frequently targeted region (e.g. in epilepsy and Alzheimer’s disease) is subject to strong, 1–2 ppm.cm(−1) regional B0, susceptibility gradients that can dramatically reduce the signal-to-noise ratio (SNR) and water suppression effectiveness. The chemical shift imaging (CSI) sequence used a 3-ms Shinnar–Le Roux (SLR) 90° RF pulse, acquiring eight steps in the slice direction. The Hadamard sequence acquired two overlapping slices using the same SLR 90° pulses, under twofold stronger gradients that proportionally halved the CSDE. Both sequences used 2D 20 × 20 rosette spectroscopic imaging (RSI) for in-plane spatial localization and both used RF and gradient performance characteristics that are easily met by all modern MRI instruments. The results show that Hadamard spectroscopic imaging (HSI) suffered dramatically less signal bleed within the VOI compared with CSI (50%) in a phantom specifically designed to test these effects. The voxels’ SNR per unit volume per unit time was also 40% higher for HSI. In a group of five healthy volunteers, we show that HSI with in-plane 2D-RSI facilitates fast, 3D multivoxel encoding at submilliliter spatial resolution, over the bilateral human hippocampus, in under 10 min, with negligible CSDE, spectral and spatial contamination and more than 6% improved SNR per unit time per unit volume.

For the spectroscopic assessment of brain disorders that require large-volume coverage, the requirements of RF performance and field homogeneity are high. For epilepsy, this is also challenging given the inter-patient variation in location, severity and subtlety of anatomical identification and its tendency to involve the temporal region. We apply a targeted method to examine the utility of large-volume MR spectroscopic imaging (MRSI) in surgical epilepsy patients, implementing a two-step acquisition, comprised of a 3D acquisition to cover the fronto-parietal regions, and a contiguous parallel two-slice Hadamard-encoded acquisition to cover the temporal-occipital region, both with T(R)/T(E) = 2000/40 ms and matched acquisition times. With restricted (static, first/second-order) B(0) shimming in their respective regions, the Cramér-Rao lower bounds for creatine from the temporal lobe two-slice Hadamard and frontal-parietal 3D acquisition are 8.1 ± 2.2% and 6.3 ± 1.9% respectively. The datasets are combined to provide a total 60 mm axial coverage over the frontal, parietal and superior temporal to middle temporal-occipital regions. We applied these acquisitions at a nominal 400 mm(3) voxel resolution in n = 27 pre-surgical epilepsy patients and n = 20 controls. In controls, 86.6 ± 3.2% voxels with at least 50% tissue (white + gray matter, excluding CSF) survived spectral quality inclusion criteria. Since all patients were clinically followed for at least 1 year after surgery, seizure frequency outcome was available for all. The MRSI measurements of the total fractional metabolic dysfunction (characterized by the Cr/NAA metric) in FreeSurfer MRI gray matter segmented regions, in the patients compared with the controls, exhibited a significant Spearman correlation with post-surgical outcome. This finding suggests that a larger burden of metabolic dysfunction is seen in patients with poorer post-surgical seizure control.

Although MRI assessment of white matter lesions is essential for the clinical management of multiple sclerosis, the processes leading to the formation of lesions and underlying their subsequent MRI appearance are incompletely understood. We used proton MR spectroscopy to study the evolution of N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho), and myo-inositol (mI) in pre-lesional tissue, persistent and transient new lesions, as well as in chronic lesions, and related the results to quantitative MRI measures of T1-hypointensity and T2-volume. Within 10 patients with relapsing-remitting course, there were 180 regions-of-interest consisting of up to seven semi-annual follow-ups of normal-appearing white matter (NAWM, n = 10), pre-lesional tissue giving rise to acute lesions which resolved (n = 3) or persisted (n = 3), and of moderately (n = 9) and severely hypointense (n = 6) chronic lesions. Compared with NAWM, pre-lesional tissue had higher Cr and Cho, while compared with lesions, pre-lesional tissue had higher NAA. Resolving acute lesions showed similar NAA levels pre- and post-formation, suggesting no long-term axonal damage. In chronic lesions, there was an increase in mI, suggesting accumulating astrogliosis. Lesion volume was a better predictor of axonal health than T1-hypointensity, with lesions larger than 1.5 cm3 uniformly exhibiting very low (

Objectives As ∼40% of HIV-infected individuals experience neurocognitive decline, we investigated whether proton magnetic resonance spectroscopic imaging (1H-MRSI) detects early metabolic abnormalities in the cerebral cortex of a simian immunodeficiency virus (SIV)-infected rhesus monkey model of neuroAIDS. Methods The brains of five rhesus monkeys before and 4 or 6 weeks after SIV infection (with CD8+ T-cell depletion) were assessed with T2-weighted quantitative magnetic resonance imaging (MRI) and 16×16×4 multivoxel 1H-MRSI (echo time/repetition time = 33/1440 ms). Grey matter and white matter masks were segmented from the animal MRIs and used to produce cortical masks co-registered to 1H-MRSI data to yield cortical metabolite concentrations of the glial markers myo-inositol (mI), creatine (Cr) and choline (Cho), and of the neuronal marker N-acetylaspartate (NAA). The cortex volume within the large, 28 cm3 (∼35% of total monkey brain) volume of interest was also calculated for each animal pre- and post-infection. Mean metabolite concentrations and cortex volumes were compared pre- and post-infection using paired sample t-tests. Results The mean (± standard deviation) pre-infection concentrations of the glial markers mI, Cr and Cho were 5.8 ± 0.9, 7.2 ± 0.4 and 0.9 ± 0.1 mM, respectively; these concentrations increased 28% (p ≈ 0.06), 15% and 10% (both p

Concentration of the neuronal marker, N-acetylaspartate (NAA), a quantitative metric for the health and density of neurons, is currently obtained by integration of the manually defined peak in whole-head proton ((1) H)-MRS. Our goal was to develop a full spectral modeling approach for the automatic estimation of the whole-brain NAA concentration (WBNAA) and to compare the performance of this approach with a manual frequency-range peak integration approach previously employed. MRI and whole-head (1) H-MRS from 18 healthy young adults were examined. Non-localized, whole-head (1) H-MRS obtained at 3 T yielded the NAA peak area through both manually defined frequency-range integration and the new, full spectral simulation. The NAA peak area was converted into an absolute amount with phantom replacement and normalized for brain volume (segmented from T1 -weighted MRI) to yield WBNAA. A paired-sample t test was used to compare the means of the WBNAA paradigms and a likelihood ratio test used to compare their coefficients of variation. While the between-subject WBNAA means were nearly identical (12.8 ± 2.5 mm for integration, 12.8 ± 1.4 mm for spectral modeling), the latter's standard deviation was significantly smaller (by ~50%, p = 0.026). The within-subject variability was 11.7% (±1.3 mm) for integration versus 7.0% (±0.8 mm) for spectral modeling, i.e., a 40% improvement. The (quantifiable) quality of the modeling approach was high, as reflected by Cramer-Rao lower bounds below 0.1% and vanishingly small (experimental - fitted) residuals. Modeling of the whole-head (1) H-MRS increases WBNAA quantification reliability by reducing its variability, its susceptibility to operator bias and baseline roll, and by providing quality-control feedback. Together, these enhance the usefulness of the technique for monitoring the diffuse progression and treatment response of neurological disorders.

Purpose To design a proton MR spectroscopy (1H-MRS) localization sequence that combines the signal-to-noise-ratio (SNR) benefits of point resolved spectroscopy (PRESS) with the high pulse bandwidths, low chemical shift displacements (CSD), low specific absorption rates (SAR), short echo times (TE), and superior radiofrequency transmit field (B1+) immunity of stimulated echo acquisition mode (STEAM), by simultaneously refocusing and acquiring both the double-spin and stimulated echo coherence pathways from the volume of interest. Theory and Methods We propose a family of 1H-MRS sequences comprising three orthogonal spatially selective pulses with flip angles 90°

PURPOSE To reduce the specific-absorption-rate (SAR) and chemical shift displacement (CSD) of three dimensional (3D) Hadamard spectroscopic imaging (HSI) and maintain its point spread function (PSF) benefits.

To test the hypotheses that global decreased neuro-axonal integrity reflected by decreased N-acetylaspartate (NAA) and increased glial activation reflected by an elevation in its marker, the myo-inositol (mI), present in a CD8-depleted rhesus macaque model of HIV-associated neurocognitive disorders. To this end, we performed quantitative MRI and 16 × 16 × 4 multivoxel proton MRS imaging (TE/TR = 33/1400 ms) in five macaques pre- and 4–6 weeks post-simian immunodeficiency virus infection. Absolute NAA, creatine, choline (Cho), and mI concentrations, gray and white matter (GM and WM) and cerebrospinal fluid fractions were obtained. Global GM and WM concentrations were estimated from 224 voxels (at 0.125 cm3 spatial resolution over ~35% of the brain) using linear regression. Pre- to post-infection global WM NAA declined 8%: 6.6 ± 0.4 to 6.0 ± 0.5 mM (p = 0.05); GM Cho declined 20%: 1.3 ± 0.2 to 1.0 ± 0.1 mM (p

Purpose: To analyze the effect of B0 field drift on multivoxel MR spectroscopic imaging and to propose an approach for its correction. Theory and Methods: It is shown, both theoretically and in a phantom, that for ∼30 min acquisitions a linear B0 drift (∼0.1 ppm/h) will cause localization errors that can reach several voxels (centimeters) in the slower varying phase encoding directions. An efficient and unbiased estimator is proposed for tracking the drift by interleaving short (∼ ), nonlocalized acquisitions on the nonsuppressed water each pulse repetition time, as shown in 10 volunteers at 1.5 and 3 T. Results: The drift is shown to be predominantly linear in both the phantom and volunteers at both fields. The localization errors are observed and quantified in both phantom and volunteers. The unbiased estimator is shown to reliably track the instantaneous frequency in vivo despite only using a small portion of the FID. Conclusion: Contrary to single-voxel MR spectroscopy, where it leads to line broadening, field drift can lead to localization errors in the longer chemical shift imaging experiments. Fortunately, this drift can be obtained at a negligible cost to sequence timing, and corrected for in post processing. Magn Reson Med, 70:895–904, 2013. © 2012 Wiley Periodicals, Inc.

Since the brain's gray matter (GM) and white matter (WM) metabolite concentrations differ, their partial volumes can vary the voxel's ¹H MR spectroscopy (¹H-MRS) signal, reducing sensitivity to changes. While single-voxel ¹H-MRS cannot differentiate between WM and GM signals, partial volume correction is feasible by MR spectroscopic imaging (MRSI) using segmentation of the MRI acquired for VOI placement. To determine the magnitude of this effect on metabolic quantification, we segmented a 1-mm³ resolution MRI into GM, WM and CSF masks that were co-registered with the MRSI grid to yield their partial volumes in approximately every 1 cm³ spectroscopic voxel. Each voxel then provided one equation with two unknowns: its i- metabolite's GM and WM concentrations C(i) (GM) , C(i) (WM) . With the voxels' GM and WM volumes as independent coefficients, the over-determined system of equations was solved for the global averaged C(i) (GM) and C(i) (WM) . Trading off local concentration differences offers three advantages: (i) higher sensitivity due to combined data from many voxels; (ii) improved specificity to WM versus GM changes; and (iii) reduced susceptibility to partial volume effects. These improvements made no additional demands on the protocol, measurement time or hardware. Applying this approach to 18 volunteered 3D MRSI sets of 480 voxels each yielded N-acetylaspartate, creatine, choline and myo-inositol C(i) (GM) concentrations of 8.5 ± 0.7, 6.9 ± 0.6, 1.2 ± 0.2, 5.3 ± 0.6 mM, respectively, and C(i) (WM) concentrations of 7.7 ± 0.6, 4.9 ± 0.5, 1.4 ± 0.1 and 4.4 ± 0.6mM, respectively. We showed that unaccounted voxel WM or GM partial volume can vary absolute quantification by 5-10% (more for ratios), which can often double the sample size required to establish statistical significance.

We propose and demonstrate a full 3D longitudinal Hadamard Spectroscopic Imaging (L-HSI) scheme for obtaining chemical shift maps, by employing adiabatic inversion pulses to encode the spins’ positions. The approach offers several advantages over conventional Fourier-based encoding methods, including a localized point spread function; no aliasing, allowing for VOIs smaller than the object being imaged; an option for acquiring non-contiguous voxels; and inherent outer volume rejection. The latter allows for doing away with conventional outer volume suppression schemes, such as PRESS or STEAM, and acquiring non spin-echo spectra with short acquisition delay times, limited only by the excitation pulse’s duration. This, in turn, minimizes T2 decay, maximizes the signal to noise ratio, and reduces J-coupling induced signal decay. Results are presented for both a phantom and an in-vivo healthy volunteer at 3T.

The longitudinal repeatability of proton MR spectroscopy ((1) H-MRS) in the healthy human brain at high fields over long periods is not established. Therefore, we assessed the inter- and intra-subject repeatability of (1) H-MRS in an approach suited for diffuse pathologies in 10 individuals, at 3T, annually for 3 years. Spectra from 480 voxels over 360 cm(3) (∼30%) of the brain, were individually phased, frequency-aligned, and summed into one average spectrum. This dramatically increases metabolites' signal-to-noise-ratios while maintaining narrow linewidths that improve quantification precision. The resulting concentrations of the N-acetylaspartate, creatine, choline, and myo-inositol are: 8.9 ± 0.8, 5.9 ± 0.6, 1.4 ± 0.1, and 4.5 ± 0.5 mM (mean ± standard-deviation). the inter-subject coefficients of variation are 8.7%, 10.2%, 10.7%, and 11.8%; and the longitudinal (intra-subject) coefficients of variation are lower still: 6.6%, 6.8%, 6.8%, and 10%, much better than the 35%, 44%, 55%, and 62% intra-voxel coefficients of variation. The biological and nonbiological components of the summed spectra coefficients of variation had similar contributions to the overall variance.

Non-human primates are often used as preclinical model systems for (mostly diffuse or multi-focal) neurological disorders and their experimental treatment. Due to cost considerations, such studies frequently utilize non-destructive imaging modalities, MRI and proton MR spectroscopy ((1) H MRS). Cost may explain why the inter- and intra-animal reproducibility of the (1) H MRS observed brain metabolites, are not reported. To this end, we performed test-retest three-dimensional brain (1) H MRS in five healthy rhesus macaques at 3 T. Spectra were acquired from 224 isotropic (0.5 cm)(3) = 125 μL voxels, over 28 cm(3) (∼ 35%) of the brain, then individually phased, frequency aligned and summed into a spectrum representative of the entire volume of interest. This dramatically increases the metabolites' signal-to-noise ratios, while maintaining the (narrow) voxel linewidth. The results show that the average N-acetylaspartate, creatine, choline, and myo-inositol concentrations in the macaque brain are: 7.7 ± 0.5, 7.0 ± 0.5, 1.2 ± 0.1 and 4.0 ± 0.6 mM/g wet weight (mean ± standard deviation). Their inter-animal coefficients of variation (CV) are 4%, 4%, 6%, and 15%; and the longitudinal (intra-animal) CVs are lower still: 4%, 5%, 5%, and 4%, much better than the 22%, 33%, 36%, and 45% intra-voxel CVs, demonstrating the advantage of the approach and its utility for preclinical studies of diffuse neurological diseases in rhesus macaques.

The accuracy of metabolic quantification in MR spectroscopy is limited by the unknown radiofrequency field and T(1). To address both issues in proton ((1)H) MR spectroscopy, we obtained radiofrequency field-corrected T(1) maps of N-acetylaspartate, choline, and creatine in five healthy rhesus macaques at 3 T. For efficient use of the 4 hour experiment, we used a new three-point protocol that optimizes the precision of T(1) in three-dimensional (1)H-MR spectroscopy localization for extensive, approximately 30%, brain coverage at 0.6 x 0.6 x 0.5 cm(3) = 180-microL spatial resolution. The resulting mean T(1)s in 700 voxels were N-acetylaspartate = 1232 +/- 44, creatine = 1238 +/- 23 and choline = 1107 +/- 56 ms (mean +/- standard error of the mean). Their histograms from all 140 voxels in each animal were similar in position and shape, characterized by standard errors of the mean of the full width at half maximum divided by their means of better than 8%. Regional gray matter N-acetylaspartate, choline, and creatine T(1)s (1333 +/- 43, 1265 +/- 52, and 1131 +/- 28 ms) were 5-10% longer than white matter: 1188 +/- 34, 1201 +/- 24, and 1082 +/- 50 ms (statistically significant for the N-acetylaspartate only), all within 10% of the corresponding published values in the human brain.

The structure and metabolism of the rhesus macaque brain, an advanced model for neurologic diseases and their treatment response, is often studied noninvasively with MRI and (1)H-MR spectroscopy. Due to the shorter transverse relaxation time (T(2)) at the higher magnetic fields these studies favor, the echo times used in (1)H-MR spectroscopy subject the metabolites to unknown T(2) weighting, decreasing the accuracy of quantification which is key for inter- and intra-animal comparisons. To establish the "baseline" (healthy animal) T(2) values, we mapped them for the three main metabolites' T(2)s at 3 T in four healthy rhesus macaques and tested the hypotheses that their mean values are similar (i) among animals; and (ii) to analogs regions in the human brain. This was done with three-dimensional multivoxel (1)H-MR spectroscopy at (0.6 x 0.6 x 0.5 cm)(3) = 180 microL spatial resolution over a 4.2 x 3.0 x 2.0 = 25 cm(3) ( approximately 30%) of the macaque brain in a two-point protocol that optimizes T(2) precision per unit time. The estimated T(2)s in several gray and white matter regions are all within 10% of those reported in the human brain (mean +/- standard error of the mean): N-acetylaspartate = 316 +/- 7, creatine = 177 +/- 3, and choline = 264 +/- 9 ms, with no statistically significant gray versus white matter differences.

Although recent studies indicate that use of a single global transverse relaxation time, T(2), per metabolite is sufficient for better than +/-10% quantification precision at intermediate and short echo-time spectroscopy in young adults, the age-dependence of this finding is unknown. Consequently, the age effect on regional brain choline (Cho), creatine (Cr), and N-acetylaspartate (NAA) T(2)s was examined in four age groups using 3D (four slices, 80 voxels 1 cm(3) each) proton MR spectroscopy in an optimized two-point protocol. Metabolite T(2)s were estimated in each voxel and in 10 gray and white matter (GM, WM) structures in 20 healthy subjects: four adolescents (13 +/- 1 years old), eight young adults (26 +/- 1); two middle-aged (51 +/- 6), and six elderly (74 +/- 3). The results reveal that T(2)s in GM (average +/- standard error of the mean) of adolescents (NAA: 301 +/- 30, Cr: 162 +/- 7, Cho: 263 +/- 7 ms), young adults (NAA: 269 +/- 7, Cr: 156 +/- 7, Cho: 226 +/- 9 ms), and elderly (NAA: 259 +/- 13, Cr: 154 +/- 8, Cho: 229 +/- 14 ms), were 30%, 16%, and 10% shorter than in WM, yielding mean global T(2)s of NAA: 343, Cr: 172, and Cho: 248 ms. The elderly NAA, Cr, and Cho T(2)s were 12%, 6%, and 10% shorter than the adolescents, a change of under 1 ms/year assuming a linear decline with age. Formulae for T(2) age-correction for higher quantification precision are provided.

Although Fourier gradient phase-encoding and Hadamard radio-frequency encoding are two established spatial MR localization techniques, the absence of voxel-shift and interpolation postprocessing algorithms for the latter has always placed it at a discouraging disadvantage. This article presents a method for voxel-shift and interpolation of Hadamard-encoded data and demonstrates both theoretically and experimentally the similarities of the respective operations between the two localization methods.

Insights into the pathogenesis of neurological disorders and the subsequent development of therapies for them may require preclinical trials in nonhuman primates whose brain anatomy, cellular composition, biochemistry, and physiology is similar to their human counterpart. Indeed, such models are used to study Parkinson's and Huntington's diseases (1,2), ischemic stroke (3), and neuroAIDS (4,5) among others. These models have shown similar metabolic changes to those in analogous regions of the human brain, making their use critical to our understanding of basic disease mechanisms and response to therapy. Such models may be particularly suitable to test therapeutic strategies using stem cell transplantation, trophic factors, and gene therapy (3,6). Compared with smaller animals, however, the cost and complexity of experiments in nonhuman primates severely restrict the number that can be used. Serial studies, therefore, favor nondestructive methods, such as MRI and proton MR spectroscopy/spectroscopic imaging (1H-MRS/MRSI). The latter modality allows assessment of neuronal cells, cell energetics, membrane turnover, gliosis, and glycolysis through their respective surrogate markers, N-acetylaspartate (NAA) (7), creatine (Cr) (8), choline (Cho), myo-inositol (mI), and lactate levels (9). Furthermore, since in vivo 1H-MRS has shown variable metabolic changes among different brain regions, 3D MRSI variants are clearly the technology of choice (10,11). These constraints combined with the much smaller primate brain require proportionally higher spatial resolution than the 1−8 cm3 common in humans (12,13) in order to resolve several analogous structures in the same scan. Additionally, they should be short enough to complete all the tests on an unharmed anesthetized animal. In this study, we report for the first time a 3D multi-voxel 1H-MRSI at 0.05 cm3 spatial resolution over ≈25% of the rhesus macaque brain with a 25-min acquisition time at 7T. The goal is to demonstrate that the above points are addressable with current state-of-the-art hardware, technology, and techniques.

Although the rhesus macaque brain is an excellent model system for the study of neurological diseases and their responses to treatment, its small size requires much higher spatial resolution, motivating use of ultra-high-field (B(0)) imagers. Their weaker radio-frequency fields, however, dictate longer pulses; hence longer TE localization sequences. Due to the shorter transverse relaxation time (T(2)) at higher B(0)s, these longer TEs subject metabolites to T(2)-weighting, that decrease their quantification accuracy. To address this we measured the T(2)s of N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) in several gray matter (GM) and white matter (WM) regions of four healthy rhesus macaques at 7T using three-dimensional (3D) proton MR spectroscopic imaging at (0.4 cm)(3) = 64 mul spatial resolution. The results show that macaque T(2)s are in good agreement with those reported in humans at 7T: 169 +/- 2.3 ms for NAA (mean +/- SEM), 114 +/- 1.9 ms for Cr, and 128 +/- 2.4 ms for Cho, with no significant differences between GM and WM. The T(2) histograms from 320 voxels in each animal for NAA, Cr, and Cho were similar in position and shape, indicating that they are potentially characteristic of "healthy" in this species.

Proton MR spectroscopic imaging (MRSI) at higher magnetic fields (B0) suffers metabolite localization errors from different chemical-shift displacements (CSDs) if spatially-selective excitation is used. This phenomenon is exacerbated by the decreasing radiofrequency (RF) field strength, B1, at higher B0s, precluding its suppression with stronger gradients. To address this, two new methods are proposed: 1) segmenting the volume-of-interest (VOI) into several slabs, allowing proportionally stronger slice-select gradients; and 2) sequentially cascading rather than superposing the components of the Hadamard selective pulses used for reasons of better point-spread function (PSF) to localize the few slices within each slab. This can reduce the peak B1 to that of a single slice. Combining these approaches permits us to increase the selective gradient four- to eightfold per given B1, to 12 or 18mT/m for 4- or 2-cm VOIs. This “brute force” approach reduces the CSD to under 0.05 cm/ppm at 7T, or less than half that at 3T. Magn Reson Med 58:167–173, 2007. © 2007 Wiley-Liss, Inc.

Quantitative MR metrics (e.g., T1, T2, diffusion coefficients, and magnetization transfer ratios (MTRs etc)) are often derived from two images collected with one acquisition parameter changed between them (the "two-point" method). Since a low signal-to-noise-ratio (SNR) adversely affects the precision of these metrics, averaging is frequently used, although improvement accrues slowly-in proportion to the square root of imaging time. Fortunately, the relationship between the images' SNRs and the metric's precision can be exploited to our advantage. Using error propagation rules, we show that for a given sequence, specifying the total imaging time uniquely determines the optimal acquisition protocol. Specifically, instead of changing only one acquisition parameter and repeating the imaging pair until all available time is spent, we propose to adjust all of the parameters and the number of averages at each point according to their contribution to the sought metric's precision. The tactic is shown to increase the precision of the well-known two-point T1, T2, and diffusion coefficients estimation by 13-90% for the same sample, sequence, hardware, and duration. It is also shown that under this general framework, precision accrues faster than the square root of time. Tables of optimal parameters are provided for various experimental scenarios.

A new strategy to yield information from the maximum number of voxels, each at the optimum signal-to-noise ratio (SNR) per unit time, in MR spectroscopic imaging (MRSI) is introduced. In the past, maximum acquisition duty-cycle was obtained by multiplexing in time several single slices each repetition time (TR), while optimal SNR was achieved by encoding the entire volume of interest (VOI) each TR. We show that optimal SNR and acquisition efficiency can both be achieved simultaneously by multiplexing in space and time several slabs of several slices, each. Since coverage of common VOIs in 3D proton MRSI in the human brain typically requires eight or more slices, at 3 T or higher magnetic fields, two or more slabs can fit into the optimum TR (∼1.6 s). Since typically four or less slices would then fit into each slab, Hadamard encoding is favored in that direction for slice profile reasons. It is demonstrated that per fixed examination length, the new method gives, at 3 T, twice as many voxels, each of the same SNR and size, compared with current 3D chemical shift imaging techniques. It is shown that this gain will increase for more extensive spatial coverage or higher fields. Magn Reson Med, 2006. © 2006 Wiley-Liss, Inc.

The point spread function (PSF) of Hadamard encoding deviates from its ideal profile due to practical (as opposed to intrinsic) reasons. Finite radiofrequency (RF) pulse length and gradient strength cause slice profile imperfections that lead to cross-talk ("voxel bleed") as large as 17% for a 1-KHz bandwidth, 5.12-ms RF pulse under 3 mT/m. This could adversely affect localization and quantification, and consequently clinical usefulness. A simple modification of the Hadamard RF pulse synthesis that exploits its unique ability to encode noncontiguous slices is proposed and shown to markedly improve the PSF. Computer simulation, in vitro and in vivo experiments confirm the theoretical derivation of voxel bleed reduction from approximately 17% to below 5% per Hadamard-encoded direction.

On October 9-11, 2003, the third meeting of the White Matter Study Group of the International Society for Magnetic Resonance in Medicine was held in Venice, Italy. This article is the report of the meeting on how to use MRI in the diagnostic workup of multiple sclerosis (MS) and allied white matter disorders, and to define the nature and the extent of MS pathology in vivo. Both of these steps are central to the design of future treatment strategies aimed at limiting the functional consequences of the most disabling aspects of this disease.

It is well known that multiple sclerosis (MS) pathogenesis continues even during periods of clinical silence. To quantify the metabolic characteristics of this activity we compared the absolute levels of N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) in the normal-appearing white matter (NAWM) between relapsing-remitting (RR) MS patients and controls. Metabolite concentrations were obtained with 3D proton MR spectroscopy at 1.5 T in a 480 cm(3) volume-of-interest (VOI), centered on the corpus callosum of 11 MS patients and 9 matched controls. Gray/white-matter/cerebral-spinal-fluid (CSF) volumes were obtained from MRI segmentation. Patients' average VOI tissue volume (V(T)), 410.8 +/- 24.0 cm(3), and metabolite levels, NAA = 6.33 +/- 0.70, Cr = 4.67 +/- 0.52, Cho = 1.40 +/- 0.17 mM, were different from the controls by -8%, -9%, +22% and +32%. The Cho level was the only single metric differentiating patients from controls at 100% specificity and >90% sensitivity. Diffusely elevated Cho and Cr probably reflect widespread microscopic inflammation, gliosis, or de- and remyelination in the NAWM. Both metabolites are potential prognostic indicators of current disease activity, preceding NAA decline and atrophy.

The inter- and intrasubject reproducibility of the metabolite levels of N-acetylaspartate (NAA), creatine (Cr), and choline (Cho), obtained with three-dimensional (3D) multivoxel proton spectroscopy (1H-MRS), was analyzed in eight healthy volunteers. Serial, back-to-back measurements on a phantom showed the methodology and instrumentation to be highly reproducible, with a median coefficient of variation (CV) of 3.8%. In the human brain, the metabolite levels' variability was larger, with intrasubject median CVs for a total of 1876 signal voxels of 13.8%, 18.5%, and 20.1% for NAA, Cr, and Cho, respectively. These variations possibly arise from small, unavoidable, ±1–2 mm volume-of-interest (VOI) repositioning uncertainties, which vary each 0.75-cm3 voxel's partial fluid/gray/white-matter fractions. Comparing the CVs between eight subjects in a total of 324 selected voxels gave total interindividual CVs of 15.6%, 23.3%, and 24.4%, compared with intraindividual CVs in the same voxels of 14.4%, 14.8%, and 15.3%, for NAA, Cr, and Cho, respectively. Replacing the signal(s) from each voxel by the average of itself with its six canonical neighbors reduces the intrasubject median CVs to 8.3%, 9.5%, and 9.7%. The measurement uncertainties can be reduced at a cost of either spatial resolution (by using larger voxels) or time (by performing serial follow-ups). Magn Reson Med 47:439–446, 2002. © 2002 Wiley-Liss, Inc.

Total N-acetyl-aspartate + N-acetyl-aspartate–glutamate (NAA), total creatine (Cr) and total choline (Cho) proton MRS (1H–MRS) signals are often used as surrogate markers in diffuse neurological pathologies, but spatial coverage of this methodology is limited to 1%–65% of the brain. Here we wish to demonstrate that non-localized, whole-head (WH) 1H–MRS captures just the brain's contribution to the Cho and Cr signals, ignoring all other compartments. Towards this end, 27 young healthy adults (18 men, 9 women), 29.9 ± 8.5 years old, were recruited and underwent T1-weighted MRI for tissue segmentation, non-localizing, approximately 3 min WH 1H–MRS (TE/TR/TI = 5/10[1]/940 ms) and 30 min 1H–MR spectroscopic imaging (MRSI) (TE/TR = 35/2100 ms) in a 360 cm3 volume of interest (VOI) at the brain's center. The VOI absolute NAA, Cr and Cho concentrations, 7.7 ± 0.5, 5.5 ± 0.4 and 1.3 ± 0.2 mM, were all within 10% of the WH: 8.6 ± 1.1, 6.0 ± 1.0 and 1.3 ± 0.2 mM. The mean NAA/Cr and NAA/Cho ratios in the WH were only slightly higher than the “brain-only” VOI: 1.5 versus 1.4 (7%) and 6.6 versus 5.9 (11%); Cho/Cr were not different. The brain/WH volume ratio was 0.31 ± 0.03 (brain ≈ 30% of WH volume). Air-tissue susceptibility-driven local magnetic field changes going from the brain outwards showed sharp gradients of more than 100 Hz/cm (1 ppm/cm), explaining the skull's Cr and Cho signal losses through resonance shifts, line broadening and destructive interference. The similarity of non-localized WH and localized VOI NAA, Cr and Cho concentrations and their ratios suggests that their signals originate predominantly from the brain. Therefore, the fast, comprehensive WH-1H-MRS method may facilitate quantification of these metabolites, which are common surrogate markers in neurological disorders.

It is commonly accepted that the signal-to-noise ratio (SNR = peak-signal/RMS-noise) per-unit-time of proton MR spectroscopy ( 1 H-MRS) is linearly proportional to the voxel volume. Consequently, with a headcoil and 30-min acquisition, 1 cm 3 is considered the SNR-limited spatial resolution barrier in the human brain. However, since local linewidths, Δυ* = (πT* 2 ) -1 , at high magnetic fields (B 0 ), are dominated by regional inhomogeneities (ΔB 0 ), i.e., T* 2 « T 2 , reducing the voxel dimensions may increase T* 2 . This could compensate, in part, for signal loss with volume decrease. It is shown that for two cubic voxels of sides I 1 and I 2 , I 1 > I 2 , as the volume decreases by (I 1 /I 2 ) 3 , their SNR ratio is reduced by only (I 1 /I 2 ) 2 due to a commensurate T * 2 increase of I 1 /I 2 . This is demonstrated in a phantom and the brains of volunteers, with 3D 1 H-MRS in a headcoil at 4 T. It is shown that while the cubic voxels' dimensions were all halved, reducing their volume eightfold, their metabolites' SNR decreased only fourfold, due to their Δυ*s' two-fold decrease. In other words, both spatial and spectral resolutions were doubled at a significantly, x2, smaller-than-expected SNR loss. This advantage was exploited to produce quality high spatial resolution, 0.75 x 0.75 x 0.75 cm 3 , metabolic maps in a 27-min acquisition.

We report acquisition of 3D image-guided localized proton spectroscopy (1H-MRS) in the human brain on a standard clinical imager. 3D coverage is achieved with a hybrid of chemical shift imaging (CSI) and transverse Hadamard spectroscopic imaging (HSI). 16 x 16 x 4 arrays of 3.5 and 1 ml voxels were obtained in 27 min. The spatially selective HSI 90 degrees pulses incorporate naturally into a PRESS double spin-echo sequence to subdivide the VOI into four partitions along its short axis. 2D CSI (16 x 16) is performed along the other long axes. Because the hybrid excites the spins in the entire VOI, a square-root-N signal-to-noise-ratio (SNR) gain per given examination time is realized compared with sequentially interleaving N 2D slices. A two-fold gain in sensitivity is demonstrated in the brain for N = 4.

Simultaneous multivoxel 31 P and 19 F 3D localized NMR spectroscopy is demonstrated on a phantom and in the liver of patients undergoing bolus-infusion 5-fluorouracil chemotherapy. The 19 F and 31 P spectra were localized with 8 x 8 x 8 3D chemical-shift imaging, with both nuclei sharing the same field of view and voxel size (27 and 64 ml in phantom and liver, respectively) using a 1.5-Tesla clinical imager with two RF channels and a dual-tuned surface coil. The repetition time (TR = 0.26 s) and Ernst nutation angles (θ E = 32° for 19 F, 28° for 31 P) were chosen to optimize the signal-to-noise ratio (SNR) per-unit time for the 0.5- to 2-s T 1 range of the 19 F and 31 P metabolites of interest. The overall examination time, including tuning, imaging, shimming and dual-nuclear spectroscopy, was under 90 min. Simultaneous acquisition of 31 P and 19 F spectra will permit the study of the influence of hepatic and/or tumor metabolism on the uptake and catabolism of fluoropyrimidine drugs with no extra measurement time. 5-fluorouracil.

Multivoxel, heteronuclear interleaved two-dimensional proton and three-dimensional 1H-decoupled 31P CSI of human brain is demonstrated. This method offers efficient use of limited examination time as patient preparation, coil tuning, shimming and imaging are done only once and the CSI data sets from both nuclei are obtained concurrently. Effective interleaving of 31P and 1H is possible due to the shorter T1s of proton brain metabolites, allowing a 1H acquisition cycle to be inserted into each 31P TR. This way, the entire MRS time is available to both nuclei, increasing their SNR per-unit-time by approximately 12% for 31P and approximately 80% for 1H, compared with sequential detection of equal (45-50 min) length. The spectral resolution and SNR of 31P are further increased through bi-level 1H-decoupling and NOE.

A technique is demonstrated to obtain interleaved proton ( 1 H) and 1 H-decoupled phosphorus ( 31 P) spectra of human brain using 2D CSI. A modified commercial full-body imager and a dual-tuned birdcage head-coil were employed. Because proton relaxation times are shorter than those of phosphorus, TR( 1 H) can be chosen to be shorter than TR( 31 P), thus permitting a 1 H acquisition to be inserted in each 31 P cycle. The scheme results in significant time savings as both CSI data sets are obtained concurrently with patient loading, coil tuning, shimming, and imaging needed to be done only once

The fluorescence and force-area behavior of chlorophyll a (Chl a) monomolecular films diluted with hydrocarbon on an aqueous subphase is reported. It is found that the diluent hexadecane, instead of conventional fatty alcohols, results in a substantial increase in the fluorescence yield of Chl a. The luminescence intensity varies nonmonotonically with respect to the intermolecular distance. A model for the mutual orientation of the chlorophyll pigments and the consequent energy transfer processes in terms of a Forster mechanism is proposed. For a random distribution of the Chl a molecules in the monolayer (k2 = 2/3) an average value of 43° is calculated for the angle between the molecular planes and the water surface. This model yields a value of 23 A for the Forster R0. Also, a value of 58° is derived for the angle between the Q-band transition moment and the line of intersection between the molecular plane and water surface. When a mixture of Chl a and Chl b in the monolayers is being excited at the absorption band of the latter pigment, typical fluorescence of Chl a is being detected. This sensitization process can also be interpreted in terms of the orientational model of the Chl molecules as presented in this work.