Daniel Spielman

All Publications

• A Phase 1 Study of Oral Vitamin D3 in Boys and Young Men With X-Linked Adrenoleukodystrophy. Neurology. Genetics Van Haren, K. P., Cunanan, K., Awani, A., Gu, M., Peña, D., Chromik, L. C., Považan, M., Rossi, N. C., Goodman, J., Sundaram, V., Winterbottom, J., Raymond, G. V., Cowan, T., Enns, G. M., Waubant, E., Steinman, L., Barker, P. B., Spielman, D., Fatemi, A. 2023; 9 (2): e200061

  Abstract

  There are no therapies for preventing cerebral demyelination in X-linked adrenoleukodystrophy (ALD). Higher plasma vitamin D levels have been linked to lower risk of inflammatory brain lesions. We assessed the safety and pharmacokinetics of oral vitamin D dosing regimens in boys and young men with ALD.In this open-label, multicenter, phase 1 study, we recruited boys and young men with ALD without brain lesions to a 12-month study of daily oral vitamin D3 supplementation. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80 ng/mL) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in the brain, measured with magnetic resonance spectroscopy, and blood, measured via mass spectrometry. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. After a midstudy safety assessment, we modified the dosing regimen, so all subsequent participants were assigned to a weight-stratified dosing regimen starting as low as 1,000 IU daily.Between October 2016 and June 2019, we enrolled 21 participants (n = 12, fixed-dose regimen; n = 9, weight-stratified regimen) with a median age of 6.7 years (range: 1.9-22 years) and median weight of 20 kg (range: 11.7-85.5 kg). The number of participants achieving target vitamin D levels was similar in both groups at 6 months (fixed dose: 92%; weight stratified: 78%) and 12 months (fixed dose: 67%; weight stratified: 67%). Among the 12 participants in the fixed-dose regimen, half had asymptomatic elevations in either urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels in the brain, but not the blood, increased significantly between baseline and 12 months.Our vitamin D dosing regimens were well tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels warrant further study as a biomarker for vitamin D and ALD.This study provides Class IV evidence that fixed or weight-stratified vitamin D supplementation achieved target levels of 25-hydroxyvitamin D in boys and young men with X-ALD without brain lesions.

  View details for DOI 10.1212/NXG.0000000000200061

  View details for PubMedID 37090939

  View details for PubMedCentralID PMC10117697

• Efficacy of Ketamine in Unmedicated Adults With Obsessive-Compulsive Disorder: A Randomized Controlled Trial Rodriguez, C., Chen, C., Glover, G., Jo, B., Spielman, D., Williams, L., Van Roessel, P., DeBattista, C., Flood, P., Ringold, A., Wintermark, M., Anderson, K., Linkovski, O., Lombardi, A., Millen, A., Pinto, A., Raila, H., Valentine, K., Filippou-Frye, M., Hawkins, J., McCarthy, E., Mukunda, P., Varias, A., Wilson, J., Wright, B. SPRINGERNATURE. 2022: 302-303

  View details for Web of Science ID 000929613800574

• Proton MRS Assessment of Neonatal Brain Metabolism During Cardiopulmonary Bypass (CPB) Surgery. NMR in biomedicine Spielman, D. M., Gu, M., Hurd, R. E., Riemer, K., Okamura, K., Hanley, F. L. 2022

  Abstract

  PURPOSE: Here we report on the development and performance of a robust 3T single-voxel proton magnetic resonance spectroscopy (1 H-MRS) experimental protocol and data analysis pipeline for quantifying brain metabolism during cardiopulmonary bypass (CPB) surgery in a neonatal porcine model, with an overall goal of elucidating primary mechanisms of brain injury associated with these procedures. The specific aims were to assess which metabolic processes can be reliably interrogated by 1 H MRS on a 3T clinical scanner and to provide an initial assessment of brain metabolism during deep hypothermia cardiac arrest (DHCA) surgery and recovery.METHODS: 14 neonatal pigs underwent CPB surgery while placed in a 3T MRI scanner for 18°C, 28°C, and 37°C DHCA studies under hyperglycemic, euglycemic, and hypoglycemic conditions. Total imaging times, including baseline measurements, circulatory arrest (CA), and recovery averaged 3 hrs/animal, during which 30 - 40 single-voxel 1 H MRS spectra (sLASER pulse sequence, TR/TE = 2000/30 ms, 64 or 128 averages) were acquired from a 2.2 cc right midbrain voxel.RESULTS: 1 H MRS at 3T was able to reliably quantify 1) anaerobic metabolism via depletion of brain glucose and the associate build-up of lactate during CA, 2) phosphocreatine (PCr) to creatine (Cr) conversion during CA and subsequent recovery upon reperfusion, 3) a robust increase in the glutamine-to-glutamate (Gln/Glu) ratio during the post-CA recovery period, and 4) a broadening of the water peak during CA.CONCLUSIONS: In vivo 1 H MRS at 3T can reliably quantify subtle metabolic brain changes previously deemed challenging to interrogate, including brain glucose concentrations even under hypoglycemic conditions, ATP usage via the conversion of PCr to Cr, and differential changes in Glu and Gln. Observed metabolic changes during CPB surgery of a neonatal porcine model provide new insights into possible mechanisms for prevention of neuronal injury.

  View details for DOI 10.1002/nbm.4752

  View details for PubMedID 35483967

• Hyperpolarized NMR study of the impact of pyruvate dehydrogenase kinase inhibition on the pyruvate dehydrogenase and TCA flux in type 2 diabetic rat muscle. Pflugers Archiv : European journal of physiology Park, J. M., Josan, S., Hurd, R. E., Graham, J., Havel, P. J., Bendahan, D., Mayer, D., Chung, Y., Spielman, D. M., Jue, T. 2021

  Abstract

  The role of pyruvate dehydrogenase in mediating lipid-induced insulin resistance stands as a central question in the pathogenesis of type 2 diabetes mellitus. Many researchers have invoked the Randle hypothesis to explain the reduced glucose disposal in skeletal muscle by envisioning an elevated acetyl CoA pool arising from increased oxidation of fatty acids. Over the years, in vivo NMR studies have challenged that monolithic view. The advent of the dissolution dynamic nuclear polarization NMR technique and a unique type 2 diabetic rat model provides an opportunity to clarify. Dynamic nuclear polarization enhances dramatically the NMR signal sensitivity and allows the measurement of metabolic kinetics in vivo. Diabetic muscle has much lower pyruvate dehydrogenase activity than control muscle, as evidenced in the conversion of [1-13C]lactate and [2-13C]pyruvate to HCO3- and acetyl carnitine. The pyruvate dehydrogenase kinase inhibitor, dichloroacetate, restores rapidly the diabetic pyruvate dehydrogenase activity to control level. However, diabetic muscle has a much larger dynamic change in pyruvate dehydrogenase flux than control. The dichloroacetate-induced surge in pyruvate dehydrogenase activity produces a differential amount of acetyl carnitine but does not affect the tricarboxylic acid flux. Further studies can now proceed with the dynamic nuclear polarization approach and a unique rat model to interrogate closely the biochemical mechanism interfacing oxidative metabolism with insulin resistance and metabolic inflexibility.

  View details for DOI 10.1007/s00424-021-02613-3

  View details for PubMedID 34415396

• Inflammatory Cytokines and Anterior Cingulate Cortex Glutamate in Adolescent Depression Segarra, J., Teresi, G., Gu, M., Spielman, D., Sacchet, M., Rosenberg-Hasson, Y., Maecker, H., Gotlib, I., Ho, T. ELSEVIER SCIENCE INC. 2021: S285

  View details for Web of Science ID 000645683800682

• Higher Levels of Pro-inflammatory Cytokines Are Associated With Higher Levels of Glutamate in the Anterior Cingulate Cortex in Depressed Adolescents. Frontiers in psychiatry Ho, T. C., Teresi, G. I., Segarra, J. R., Ojha, A., Walker, J. C., Gu, M., Spielman, D. M., Sacchet, M. D., Jiang, F., Rosenberg-Hasson, Y., Maecker, H., Gotlib, I. H. 2021; 12: 642976

  Abstract

  Animal models of stress and related conditions, including depression, have shown that elevated peripheral levels of inflammatory cytokines have downstream consequences on glutamate (Glu) in the brain. Although studies in human adults with depression have reported evidence of higher inflammation but lower Glu in the anterior cingulate cortex (ACC), the extent to which peripheral inflammation contributes to glutamatergic abnormalities in adolescents with depression is not well-understood. It is also unclear whether antioxidants, such as ascorbate (Asc), may buffer against the effects of inflammation on Glu metabolism. Fifty-five depressed adolescents were recruited in the present cross-sectional study and provided blood samples, from which we assayed pro-inflammatory cytokines, and underwent a short-TE proton magnetic spectroscopy scan at 3T, from which we estimated Glu and Asc in the dorsal ACC. In the 31 adolescents with usable cytokine and Glu data, we found that IL-6 was significantly positively associated with dorsal ACC Glu (beta = 0.466 ± 0.199, p = 0.029). Of the 16 participants who had usable Asc data, we found that at higher levels of dorsal ACC Asc, there was a negative association between IL-6 and Glu (interaction effect: beta = -0.906 ± 0.433, p = 0.034). Importantly, these results remained significant when controlling for age, gender, percentage of gray matter in the dorsal ACC voxel, BMI, and medication (antidepressant and anti-inflammatory) usage. While preliminary, our results underscore the importance of examining both immune and neural contributors to depression and highlight the potential role of anti-inflammatory compounds in mitigating the adverse effects of inflammation (e.g., glutamatergic neuroexcitotoxicity). Future studies that experimentally manipulate levels of inflammation, and of ascorbate, and that characterize these effects on cortical glutamate concentrations and subsequent behavior in animals and in humans are needed.

  View details for DOI 10.3389/fpsyt.2021.642976

  View details for PubMedID 33935833

• Study Protocol for Teen Inflammation Glutamate Emotion Research (TIGER). Frontiers in human neuroscience Walker, J. C., Teresi, G. I., Weisenburger, R. L., Segarra, J. R., Ojha, A., Kulla, A., Sisk, L., Gu, M., Spielman, D. M., Rosenberg-Hasson, Y., Maecker, H. T., Singh, M. K., Gotlib, I. H., Ho, T. C. 2020; 14: 585512

  Abstract

  This article provides an overview of the study protocol for the Teen Inflammation Glutamate Emotion Research (TIGER) project, a longitudinal study in which we plan to recruit 60 depressed adolescents (ages 13-18 years) and 30 psychiatrically healthy controls in order to examine the inflammatory and glutamatergic pathways that contribute to the recurrence of depression in adolescents. TIGER is the first study to examine the effects of peripheral inflammation on neurodevelopmental trajectories by assessing changes in cortical glutamate in depressed adolescents. Here, we describe the scientific rationale, design, and methods for the TIGER project. This article is intended to serve as an introduction to this project and to provide details for investigators who may be seeking to replicate or extend these methods for other related research endeavors.

  View details for DOI 10.3389/fnhum.2020.585512

  View details for PubMedID 33192421

  View details for PubMedCentralID PMC7604389

• Study Protocol for Teen Inflammation Glutamate Emotion Research (TIGER) FRONTIERS IN HUMAN NEUROSCIENCE Walker, J. C., Teresi, G. I., Weisenburger, R. L., Segarra, J. R., Ojha, A., Kulla, A., Sisk, L., Gu, M., Spielman, D. M., Rosenberg-Hasson, Y., Maecker, H. T., Singh, M. K., Gotlib, I. H., Ho, T. C. 2020; 14

  View details for DOI 10.3389/fnhum.2020.585512

  View details for Web of Science ID 000583260500001

• MRI of [2-13 C]Lactate without J-coupling artifacts. Magnetic resonance in medicine Datta, K., Spielman, D. 2020

  Abstract

  PURPOSE: Imaging of [2-13 C]lactate, a metabolic product of [2-13 C]pyruvate, is over considerable interest in hyperpolarized 13 C studies. However, artifact-free imaging of a J-coupled nuclear spin species can be challenging due to the peak-splitting induced by the spin-spin interactions. In this work, two new techniques resolving these J-modulated artifacts are presented.THEORY AND METHODS: The Product Operator Formalism (POF) of density matrix theory is used to both numerically and analytically derive the coherences arising during radiofrequency excitation and readout of a J-coupled spin system. A combination of computer simulations and experiments with [2-13 C]lactate and 13 C-formate phantoms are then used to verify the performance of two imaging methods. In the first approach, a quadrature imaging technique is used to eliminate scalar coupling artifacts via the combination of in-phase and quadrature images acquired at echo times differing by 1/2J with an echoplanar readout. The second approach employs a highly narrowband RF excitation pulse to image a single peak from the J-coupled doublet.RESULTS: Simulations using a numerical Shepp-Logan phantom, in vitro experiments using thermally polarized [2-13 C]lactate, thermally and hyperpolarized 13 C-formate phantoms, and in vivo imaging of [2-13 C]lactate produced in rat brain following injection of hyperpolarized [2-13 C]pyruvate show artifact-free images and demonstrate potential utility of these methods.CONCLUSION: The quadrature imaging and the narrowband excitation techniques resolve the J-coupling induced ghosting and blurring artifacts present with conventional MRI of J-coupled signals such as [2-13 C]lactate.

  View details for DOI 10.1002/mrm.28532

  View details for PubMedID 33058240

• GABA Measurement in a Neonatal Fragile X Syndrome Mouse Model Using 1H-Magnetic Resonance Spectroscopy and Mass Spectrometry. Frontiers in molecular neuroscience Reyes, S. T., Mohajeri, S. n., Krasinska, K. n., Guo, S. G., Gu, M. n., Pisani, L. n., Rosenberg, J. n., Spielman, D. M., Chin, F. T. 2020; 13: 612685

  Abstract

  Fragile X syndrome (FXS) is the leading monogenetic cause of autism spectrum disorder and inherited cause of intellectual disability that affects approximately one in 7,000 males and one in 11,000 females. In FXS, the Fmr1 gene is silenced and prevents the expression of the fragile X mental retardation protein (FMRP) that directly targets mRNA transcripts of multiple GABAA subunits. Therefore, FMRP loss adversely impacts the neuronal firing of the GABAergic system which creates an imbalance in the excitatory/inhibitory ratio within the brain. Current FXS treatment strategies focus on curing symptoms, such as anxiety or decreased social function. While treating symptoms can be helpful, incorporating non-invasive imaging to evaluate how treatments change the brain's biology may explain what molecular aberrations are associated with disease pathology. Thus, the GABAergic system is suitable to explore developing novel therapeutic strategies for FXS. To understand how the GABAergic system may be affected by this loss-of-function mutation, GABA concentrations were examined within the frontal cortex and thalamus of 5-day-old wild type and Fmr1 knockout mice using both 1H magnetic resonance imaging (1H-MRS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our objective was to develop a reliable scanning method for neonatal mice in vivo and evaluate whether 1H-MRS is suitable to capture regional GABA concentration differences at the front end of the critical cortical period where abnormal neurodevelopment occurs due to FMRP loss is first detected. 1H-MRS quantified GABA concentrations in both frontal cortex and thalamus of wild type and Fmr1 knockout mice. To substantiate the results of our 1H-MRS studies, in vitro LC-MS/MS was also performed on brain homogenates from age-matched mice. We found significant changes in GABA concentration between the frontal cortex and thalamus within each mouse from both wild type and Fmr1 knockout mice using 1H-MRS and LC-MS/MS. Significant GABA levels were also detected in these same regions between wild type and Fmr1 knockout mice by LC-MS/MS, validating that FMRP loss directly affects the GABAergic system. Thus, these new findings support the need to develop an effective non-invasive imaging method to monitor novel GABAergic strategies aimed at treating patients with FXS.

  View details for DOI 10.3389/fnmol.2020.612685

  View details for PubMedID 33390902

  View details for PubMedCentralID PMC7775297

• Water and lipid suppression techniques for advanced 1 H MRS and MRSI of the human brain: Experts' consensus recommendations. NMR in biomedicine Tkáč, I. n., Deelchand, D. n., Dreher, W. n., Hetherington, H. n., Kreis, R. n., Kumaragamage, C. n., Považan, M. n., Spielman, D. M., Strasser, B. n., de Graaf, R. A. 2020: e4459

  Abstract

  The neurochemical information provided by proton magnetic resonance spectroscopy (MRS) or MR spectroscopic imaging (MRSI) can be severely compromised if strong signals originating from brain water and extracranial lipids are not properly suppressed. The authors of this paper present an overview of advanced water/lipid-suppression techniques and describe their advantages and disadvantages. Moreover, they provide recommendations for choosing the most appropriate techniques for proper use. Methods of water signal handling are primarily focused on the VAPOR technique and on MRS without water suppression (metabolite cycling). The section on lipid-suppression methods in MRSI is divided into three parts. First, lipid-suppression techniques that can be implemented on most clinical MR scanners (volume preselection, outer-volume suppression, selective lipid suppression) are described. Second, lipid-suppression techniques utilizing the combination of k-space filtering, high spatial resolutions and lipid regularization are presented. Finally, three promising new lipid-suppression techniques, which require special hardware (a multi-channel transmit system for dynamic B1+ shimming, a dedicated second-order gradient system or an outer volume crusher coil) are introduced.

  View details for DOI 10.1002/nbm.4459

  View details for PubMedID 33327042

• Thalamic and prefrontal GABA concentrations but not GABAA receptor densities are altered in high-functioning adults with autism spectrum disorder. Molecular psychiatry Fung, L. K., Flores, R. E., Gu, M. n., Sun, K. L., James, D. n., Schuck, R. K., Jo, B. n., Park, J. H., Lee, B. C., Jung, J. H., Kim, S. E., Saggar, M. n., Sacchet, M. D., Warnock, G. n., Khalighi, M. M., Spielman, D. n., Chin, F. T., Hardan, A. Y. 2020

  Abstract

  The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [18F]flumazenil positron emission tomography ([18F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (1H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, 1H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger's Diagnostic Scale-Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water's relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

  View details for DOI 10.1038/s41380-020-0756-y

  View details for PubMedID 32376999

• Multimodality Hyperpolarized C-13 MRS/PET/Multiparametric MR Imaging for Detection and Image-Guided Biopsy of Prostate Cancer: First Experience in a Canine Prostate Cancer Model MOLECULAR IMAGING AND BIOLOGY Bachawal, S. V., Park, J., Valluru, K. S., Loft, M., Felt, S. A., Vilches-Moure, J. G., Saenz, Y. F., Daniel, B., Iagaru, A., Sonn, G., Cheng, Z., Spielman, D. M., Willmann, J. K. 2019; 21 (5): 861–70

  View details for DOI 10.1007/s11307-018-1235-6

  View details for Web of Science ID 000483788100009

• Effects of acute N-acetylcysteine challenge on cortical glutathione and glutamate in schizophrenia: A pilot in vivo proton magnetic resonance spectroscopy study PSYCHIATRY RESEARCH Girgis, R. R., Baker, S., Mao, X., Gil, R., Javitt, D. C., Kantrowitz, J. T., Gu, M., Spielman, D. M., Ojeil, N., Xu, X., Abi-Dargham, A., Shungu, D. C., Kegeles, L. S. 2019; 275: 78–85

  View details for DOI 10.1016/j.psychres.2019.03.018

  View details for Web of Science ID 000469156400011

• Detection of Metabolic Changes using Hyperpolarized C-13 MRI in a Negative F-18-FDG PET Rat Brain Cancer Model Lauritzen, M., Datta, K., Merchant, M., Jang, T., Hurd, R., Liu, S., Recht, L., Spielman, D. SOC NUCLEAR MEDICINE INC. 2019

  View details for Web of Science ID 000473116801214

• Effects of acute N-acetylcysteine challenge on cortical glutathione and glutamate in schizophrenia: A pilot in vivo proton magnetic resonance spectroscopy study. Psychiatry research Girgis, R. R., Baker, S., Mao, X., Gil, R., Javitt, D. C., Kantrowitz, J. T., Gu, M., Spielman, D. M., Ojeil, N., Xu, X., Abi-Dargham, A., Shungu, D. C., Kegeles, L. S. 2019; 275: 78–85

  Abstract

  Findings from in vivo brain proton magnetic resonance spectroscopy (1H MRS) and preclinical studies have suggested region- and medication status-dependent increases in glutamate (Glu) levels and deficiencies in glutathione (GSH) levels in schizophrenia. N-acetylcysteine (NAC), a GSH synthesis precursor, has demonstrated modest clinical benefit in schizophrenia. The objective of this study was to examine the effects of acute administration of NAC on GSH and Glu levels measured with 1H MRS in 19 patients with schizophrenia and 20 healthy control subjects. Levels of GSH were acquired in dorsal anterior cingulate cortex (dACC), and those of Glu in dACC and medial prefrontal cortex (mPFC), at baseline and 60 min following acute oral administration of 2400 mg of NAC. No differences in the levels of GSH or Glu were found at baseline or following NAC administration between patients with schizophrenia and control subjects in either of the targeted brain regions. Future studies measuring GSH levels in brain regions previously found to exhibit glutamatergic abnormalities or using genetic polymorphisms, while controlling for the age and medication status of the cohorts, are warranted to better identify groups of patients more likely to respond to NAC and its mode of action and mechanisms.

  View details for PubMedID 30884334

• Multimodality Hyperpolarized C-13 MRS/PET/Multiparametric MR Imaging for Detection and Image-Guided Biopsy of Prostate Cancer: First Experience in a Canine Prostate Cancer Model. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Bachawal, S. V., Park, J. M., Valluru, K. S., Loft, M. D., Felt, S. A., Vilches-Moure, J. G., Saenz, Y. F., Daniel, B., Iagaru, A., Sonn, G., Cheng, Z., Spielman, D. M., Willmann, J. K. 2019

  Abstract

  PURPOSE: To assess whether simultaneous hyperpolarized C-13 magnetic resonance spectroscopy (MRS)/positron emission tomography (PET)/multiparametric magnetic resonance (mpMR) imaging is feasible in an orthotopic canine prostate cancer (PCa) model using a clinical PET/MR system and whether the combined imaging datasets can be fused with transrectal ultrasound (TRUS) in real time for multimodal image fusion-guided targeted biopsy of PCa.PROCEDURES: Institutional Animal Care and Use Committee approval was obtained for this study. Canine prostate adenocarcinoma (Ace-1) cells were orthotopically injected into the prostate of four dogs. Once tumor engraftment was confirmed by TRUS, simultaneous hyperpolarized C-13 MRS of [1-13C]pyruvate, PET (2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), [68Ga]NODAGA-SCH1), and mpMR (T2W, DWI) imaging was performed using a clinical PET/MR system. Multimodality imaging data sets were then fused with TRUS and image-guided targeted biopsy was performed. Imaging results were then correlated with histological findings.RESULTS: Successful tumor engraftment was histologically confirmed in three of the four dogs (dogs 2, 3, and 4) and simultaneous C-13 MRS/PET/mpMR was feasible in all three. In dog 2, C-13 MRS showed increased lactate signal in the tumor (lactate/totalC=0.47) whereas mpMR did not show any signal changes. In dog 3, [18F]FDG-PET (SUVmean=1.90) and C-13 MRS (lactate/totalC=0.59) showed elevated metabolic activity in the tumor. In dog 4, [18F]FDG (SUVmean=2.43), [68Ga]NODAGA-SCH1 (SUVmean=0.75), and C-13 MRS (Lac/totalC=0.53) showed elevated uptake in tumor compared to control tissue and multimodal image fusion-guided biopsy of the tumor was successfully performed.CONCLUSION: Simultaneous C-13 MRS/PET/mpMR imaging and multimodal image fusion-guided biopsy is feasible in a canine PCa model.

  View details for PubMedID 30793241

• Comparison of dynamic brain metabolism during antegrade cerebral perfusion versus deep hypothermic circulatory arrest using proton magnetic resonance spectroscopy. The Journal of thoracic and cardiovascular surgery Hanley, F. L., Ito, H. n., Gu, M. n., Hurd, R. n., Riemer, R. K., Spielman, D. n. 2019

  View details for DOI 10.1016/j.jtcvs.2019.10.103

  View details for PubMedID 31780069

• Hyperpolarized C-13 MRI: Path to Clinical Translation in Oncology NEOPLASIA Kurhanewicz, J., Vigneron, D. B., Ardenkjaer-Larsen, J., Bankson, J. A., Brindle, K., Cunningham, C. H., Gallagher, F. A., Keshari, K. R., Kjaer, A., Laustsen, C., Mankoff, D. A., Merritt, M. E., Nelson, S. J., Pauly, J. M., Lee, P., Ronen, S., Tyler, D. J., Rajan, S. S., Spielman, D. M., Wald, L., Zhang, X., Malloy, C. R., Rizi, R. 2019; 21 (1): 1–16

  View details for DOI 10.1016/j.neo.2018.09.006

  View details for Web of Science ID 000454509400001

• Reversed metabolic reprogramming as a measure of cancer treatment efficacy in rat C6 glioma model. PloS one Datta, K. n., Lauritzen, M. H., Merchant, M. n., Jang, T. n., Liu, S. C., Hurd, R. n., Recht, L. n., Spielman, D. M. 2019; 14 (12): e0225313

  Abstract

  Metabolism in tumor shifts from oxidative phosphorylation to inefficient glycolysis resulting in overproduction of lactate (Warburg effect), and cancers may be effectively treated if this imbalance were corrected. The aim of this longitudinal study of glioblastoma in a rat model was to determine whether the ratio of lactate (surrogate marker for glycolysis) to bicarbonate (for oxidative phosphorylation), as measured via in vivo magnetic resonance imaging of hyperpolarized 13C-labeled pyruvate accurately predicts survival.C6 Glioma implanted male Wistar rats (N = 26) were treated with an anti-vascular endothelial growth factor antibody B20.4.1.1 in a preliminary study to assess the efficacy of the drug. In a subsequent longitudinal survival study, magnetic resonance spectroscopic imaging (MRSI) was used to estimate [1-13C]Lactate and [1-13C]Bicarbonate in tumor and contralateral normal appearing brain of glioma implanted rats (N = 13) after injection of hyperpolarized [1-13C]Pyruvate at baseline and 48 hours post-treatment with B20.4.1.1.A survival of ~25% of B20.4.1.1 treated rats was noted in the preliminary study. In the longitudinal imaging experiment, changes in 13C Lactate, 13C Bicarbonate and tumor size measured at baseline and 48 hours post-treatment did not correlate with survival. 13C Lactate to 13C Bicarbonate ratio increased in all the 6 animals that succumbed to the tumor whereas the ratio decreased in 6 of the 7 animals that survived past the 70-day observation period.13C Lactate to 13C Bicarbonate ratio (Lac/Bic) at 48 hours post-treatment is highly predictive of survival (p = 0.003). These results suggest a potential role for the 13C Lac/Bic ratio serving as a valuable measure of tumor metabolism and predicting therapeutic response.

  View details for DOI 10.1371/journal.pone.0225313

  View details for PubMedID 31830049

• Socio-Communicative Deficits are Modulated by GABA Concentrations but Not GABA(A) Receptor Densities in Adults With Autism Spectrum Disorder Fung, L., Flores, R., Gu, M., Spielman, D., Chin, F., Hardan, A. NATURE PUBLISHING GROUP. 2018: S317

  View details for Web of Science ID 000509546600584

• Hyperpolarized 13C MRI: Path to Clinical Translation in Oncology. Neoplasia (New York, N.Y.) Kurhanewicz, J., Vigneron, D. B., Ardenkjaer-Larsen, J. H., Bankson, J. A., Brindle, K., Cunningham, C. H., Gallagher, F. A., Keshari, K. R., Kjaer, A., Laustsen, C., Mankoff, D. A., Merritt, M. E., Nelson, S. J., Pauly, J. M., Lee, P., Ronen, S., Tyler, D. J., Rajan, S. S., Spielman, D. M., Wald, L., Zhang, X., Malloy, C. R., Rizi, R. 2018; 21 (1): 1–16

  Abstract

  This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13C MRI in 2011, preclinical studies involving [1-13C]pyruvate as well a number of other 13C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-13C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.

  View details for PubMedID 30472500

• Metabolic markers, regional adiposity, and adipose cell size: relationship to insulin resistance in African-American as compared with Caucasian women. International journal of obesity (2005) Allister-Price, C. n., Craig, C. M., Spielman, D. n., Cushman, S. S., McLaughlin, T. L. 2018

  Abstract

  African-American women have the greatest prevalence of obesity in the United States, and higher rates of type 2 diabetes than Caucasian women, yet paradoxically lower plasma triglycerides (TG), visceral fat and intrahepatic fat, and higher high-density lipoprotein (HDL)-cholesterol. Visceral fat has not been evaluated against insulin resistance in African-American women, and TG/HDL-cholesterol has been criticized as a poor biomarker for insulin resistance in mixed-sex African-American populations. Adipocyte hypertrophy, reflecting adipocyte dysfunction, predicts insulin resistance in Caucasians, but has not been studied in African-Americans. Our goal was to assess whether traditional correlates of insulin resistance, measures of adiposity and adipocyte characteristics similarly predict peripheral insulin resistance in African-American and Caucasian women.Thirty-four healthy African-American (n = 17) and Caucasian (n = 17) women, matched for age (mean = 53.0 yrs) and body mass index (BMI) (mean = 30 kg/m2), underwent a steady-state plasma glucose test to measure insulin sensitivity; computed tomography (fat distribution); and a periumbilical scalpel biopsy (adipocyte characterization). By-race analyzes utilized analysis of covariance; linear regressions evaluated relationships between metabolic/adipose variables. All analyses adjusted for BMI and menopausal status.Insulin sensitivity did not differ between groups (p = 0.65). Neither BMI, nor %body fat or thigh fat predicted insulin resistance in African-American women. Fasting TG (p = 0.046), HDL-cholesterol (p = 0.0006) and TG/HDL-cholesterol ratio (p = 0.009) strongly predicted insulin resistance in African-American women. Despite being lower in African-American women, hepatic fat and visceral adipose tissue (VAT) correlated with insulin resistance in both groups, as did fasting glucose, VAT/SAT (subcutaneous adipose tissue) ratio, and %SAT (inverse).Total adiposity measures and adipocyte hypertrophy did not predict insulin resistance in African-American women, but did in Caucasian women. Plasma TG and HDL-cholesterol were significant predictors of insulin resistance in African-American women. Our findings demonstrate the need to identify race and sex-specific biomarkers for metabolic risk profiling.

  View details for PubMedID 30127463

• A Metabolic Therapy for Malignant Glioma Requires a Clinical Measure CURRENT ONCOLOGY REPORTS Corbin, Z., Spielman, D., Recht, L. 2017; 19 (12): 84

  Abstract

  Cancers are "reprogrammed" to use a much higher rate of glycolysis (GLY) relative to oxidative phosphorylation (OXPHOS), even in the presence of adequate amounts of oxygenation. Originally identified by Nobel Laureate Otto Warburg, this hallmark of cancer has recently been termed metabolic reprogramming and represents a way for the cancer tissue to divert carbon skeletons to produce biomass. Understanding the mechanisms that underlie this metabolic shift should lead to better strategies for cancer treatments. Malignant gliomas, cancers that are very resistant to conventional treatments, are highly glycolytic and seem particularly suited to approaches that can subvert this phenotype.

  View details for PubMedID 29098465

• Comprehensive Examination of the GABAergic System in Adults With Autism by Simultaneous [18F] Flumazenil-Positron Emission Tomography and Magnetic Resonance Spectroscopy Fung, L., Flores, R., Liu, K., Gu, M., Spielman, D., Chin, F., Hardan, A. NATURE PUBLISHING GROUP. 2017: S206–S207

  View details for Web of Science ID 000416846301148

• CEREBRAL BLOW FLOW AND SUV TRENDS IN PET/MRI FOLLOWING BEVACIZUMAB ADMINISTRATION IN GLIOBLASTOMA Corbin, Z. A., Zaharchuk, G., Spielman, D. M., Recht, L. D. OXFORD UNIV PRESS INC. 2017: 158

  View details for Web of Science ID 000415152503007

• PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxy-D-glucose ONCOTARGET Tee, S., Park, J., Hurd, R. E., Brimacombe, K. R., Boxer, M. B., Massoud, T. F., Rutt, B. K., Spielman, D. M. 2017; 8 (53): 90959–68

  View details for DOI 10.18632/oncotarget.19630

  View details for Web of Science ID 000414175500040

• PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxy-D-glucose. Oncotarget Tee, S. S., Park, J. M., Hurd, R. E., Brimacombe, K. R., Boxer, M. B., Massoud, T. F., Rutt, B. K., Spielman, D. M. 2017; 8 (53): 90959-90968

  Abstract

  Cancer metabolism has emerged as an increasingly attractive target for interfering with tumor growth. Small molecule activators of pyruvate kinase isozyme M2 (PKM2) suppress tumor formation but have an unknown effect on established tumors. We demonstrate that TEPP-46, a PKM2 activator, results in increased glucose consumption, providing the rationale for combining PKM2 activators with the toxic glucose analog, 2-deoxy-D-glucose (2-DG). Combination treatment resulted in reduced viability of a range of cell lines in standard cell culture conditions at concentrations of drugs that had no effect when used alone. This effect was replicated in vivo on established subcutaneous tumors. We further demonstrated the ability to detect acute metabolic differences in combination treatment using hyperpolarized magnetic resonance spectroscopy (MRS). Combination treated tumors displayed a higher pyruvate to lactate 13C-label exchange 2 hr post-treatment. This ability to assess the effect of drugs non-invasively may accelerate the implementation and clinical translation of drugs that target cancer metabolism.

  View details for DOI 10.18632/oncotarget.19630

  View details for PubMedID 29207616

  View details for PubMedCentralID PMC5710897

• C-Thiourea. ACS chemical biology Wibowo, A., Park, J. M., Liu, S., Khosla, C., Spielman, D. M. 2017

  Abstract

  Reactive oxygen species (ROS) are essential cellular metabolites widely implicated in many diseases including cancer, inflammation, and cardiovascular and neurodegenerative disorders. Yet, ROS signaling remains poorly understood, and their measurements are a challenge due to high reactivity and instability. Here, we report the development of (13)C-thiourea as a probe to detect and measure H2O2 dynamics with high sensitivity and spatiotemporal resolution using hyperpolarized (13)C magnetic resonance spectroscopic imaging. In particular, we show (13)C-thiourea to be highly polarizable and to possess a long spin-lattice relaxation time (T1), which enables real-time monitoring of ROS-mediated transformation. We also demonstrate that (13)C-thiourea reacts readily with H2O2 to give chemically distinguishable products in vitro and validate their detection in vivo in a mouse liver. This study suggests that (13)C-thiourea is a promising agent for noninvasive detection of H2O2 in vivo. More broadly, our findings outline a viable clinical application for H2O2 detection in patients with a range of diseases.

  View details for DOI 10.1021/acschembio.7b00130

  View details for PubMedID 28452454

• Hyperpolarized Sodium [1-C-13]-Glycerate as a Probe for Assessing Glycolysis In Vivo JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Park, J., Wu, M., Datta, K., Liu, S., Castillo, A., Lough, H., Spielman, D. M., Billingsley, K. L. 2017; 139 (19): 6629–34

  Abstract

  Hyperpolarized 13C magnetic resonance spectroscopy (MRS) provides unprecedented opportunities to obtain clinical diagnostic information through in vivo monitoring of metabolic pathways. The continuing advancement of this field relies on the identification of molecular probes that can effectively interrogate pathways critical to disease. In this report, we describe the synthesis, development, and in vivo application of sodium [1-13C]-glycerate ([13C]-Glyc) as a novel probe for evaluating glycolysis using hyperpolarized 13C MRS. This agent was prepared by a concise synthetic route and formulated for dynamic nuclear polarization. [13C]-Glyc displayed a high level of polarization and long spin-lattice relaxation time-both of which are necessary for future clinical investigations. In vivo spectroscopic studies with hyperpolarized [13C]-Glyc in rat liver furnished metabolic products, [13C]-labeled pyruvate and lactate, originating from glycolysis. The levels of production and relative intensities of these metabolites were directly correlated with the induced glycolytic state (fasted versus fed groups). This work establishes hyperpolarized [13C]-Glyc as a novel agent for clinically relevant 13C MRS studies of energy metabolism and further provides opportunities for evaluating intracellular redox states in biochemical investigations.

  View details for PubMedID 28467066

• Simultaneous [18F]Flumazenil-Positron Emission Tomography and GABA-Magnetic Resonance Spectroscopy in Adults with Autism and Healthy Volunteers Fung, L., Flores, R., Gu, M., Hjoernevik, T., Hardan, A., Spielman, D., Chin, F. ELSEVIER SCIENCE INC. 2017: S127–S128

  View details for DOI 10.1016/j.biopsych.2017.02.325

  View details for Web of Science ID 000400348700311

• C]Alanine. Magnetic resonance in medicine Park, J. M., Khemtong, C., Liu, S., Hurd, R. E., Spielman, D. M. 2017; 77 (5): 1741-1748

  Abstract

  The intracellular lactate to pyruvate concentration ratio is a commonly used tissue assay biomarker of redox, being proportional to free cytosolic [NADH]/[NAD(+) ]. In this study, we assessed the use of hyperpolarized [1-(13) C]alanine and the subsequent detection of the intracellular products of [1-(13) C]pyruvate and [1-(13) C]lactate as a useful substrate for assessing redox levels in the liver in vivo.Animal experiments were conducted to measure in vivo metabolism at baseline and after ethanol infusion. A solution of 80-mM hyperpolarized [1-(13) C]alanine was injected intravenously at baseline (n = 8) and 45 min after ethanol infusion (n = 4), immediately followed by the dynamic acquisition of (13) C MRS spectra.In vivo rat liver spectra showed peaks from [1-(13) C] alanine and the products of [1-(13) C]lactate, [1-(13) C]pyruvate, and (13) C-bicarbonate. A significantly increased (13) C-lactate/(13) C-pyruvate ratio was observed after ethanol infusion (8.46 ± 0.58 at baseline versus 13.58 ± 0.69 after ethanol infusion; P < 0.001) consistent with the increased NADH produced by liver metabolism of ethanol to acetaldehyde and then acetate. A decrease in (13) C-bicarbonate production was also noted, potentially reflecting ethanol-induced mitochondrial redox changes.A method to measure in vivo tissue redox using hyperpolarized [1-(13) C]alanine is presented, with the validity of the proposed (13) C-pyruvate/(13) C-lactate metric tested using an ethanol challenge to alter liver redox state. Magn Reson Med 77:1741-1748, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

  View details for DOI 10.1002/mrm.26662

  View details for PubMedID 28261868

• In vivo assessment of intracellular redox state in rat liver using hyperpolarized [1-C-13]Alanine MAGNETIC RESONANCE IN MEDICINE Park, J. M., Khemtong, C., Liu, S., Hurd, R. E., Spielman, D. M. 2017; 77 (5): 1741-1748

  Abstract

  The intracellular lactate to pyruvate concentration ratio is a commonly used tissue assay biomarker of redox, being proportional to free cytosolic [NADH]/[NAD(+) ]. In this study, we assessed the use of hyperpolarized [1-(13) C]alanine and the subsequent detection of the intracellular products of [1-(13) C]pyruvate and [1-(13) C]lactate as a useful substrate for assessing redox levels in the liver in vivo.Animal experiments were conducted to measure in vivo metabolism at baseline and after ethanol infusion. A solution of 80-mM hyperpolarized [1-(13) C]alanine was injected intravenously at baseline (n = 8) and 45 min after ethanol infusion (n = 4), immediately followed by the dynamic acquisition of (13) C MRS spectra.In vivo rat liver spectra showed peaks from [1-(13) C] alanine and the products of [1-(13) C]lactate, [1-(13) C]pyruvate, and (13) C-bicarbonate. A significantly increased (13) C-lactate/(13) C-pyruvate ratio was observed after ethanol infusion (8.46 ± 0.58 at baseline versus 13.58 ± 0.69 after ethanol infusion; P < 0.001) consistent with the increased NADH produced by liver metabolism of ethanol to acetaldehyde and then acetate. A decrease in (13) C-bicarbonate production was also noted, potentially reflecting ethanol-induced mitochondrial redox changes.A method to measure in vivo tissue redox using hyperpolarized [1-(13) C]alanine is presented, with the validity of the proposed (13) C-pyruvate/(13) C-lactate metric tested using an ethanol challenge to alter liver redox state. Magn Reson Med 77:1741-1748, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

  View details for DOI 10.1002/mrm.26662

  View details for Web of Science ID 000399666400002

• Interrogating the GABAergic system with simultaneous [F-18]-Flumazenilpositron emission tomography and GABA-magnetic resonance spectroscopy in healthy volunteers Fung, L., Flores, R., Gu, M., Leuze, C., Hjoernevik, T., Shen, B., Park, J., Jung, J. H., Lee, B. C., Kim, S. E., McNab, J., Srinivas, S., Spielman, D., Chin, F. SAGE PUBLICATIONS INC. 2017: 214-215

  View details for Web of Science ID 000400157400314

• GABA editing with macromolecule suppression using an improved MEGA-SPECIAL sequence. Magnetic resonance in medicine Gu, M., Hurd, R., Noeske, R., Baltusis, L., Hancock, R., Sacchet, M. D., Gotlib, I. H., Chin, F. T., Spielman, D. M. 2017

  Abstract

  The most common γ-aminobutyric-acid (GABA) editing approach, MEGA-PRESS, uses J-editing to measure GABA distinct from larger overlapping metabolites, but suffers contamination from coedited macromolecules (MMs) comprising 40 to 60% of the observed signal. MEGA-SPECIAL is an alternative method with better MM suppression, but is not widely used primarily because of its relatively poor spatial localization. Our goal was to develop an improved MM-suppressed GABA editing sequence at 3 Tesla.We modified a single-voxel MEGA-SPECIAL sequence with an oscillating readout gradient for improved spatial localization, and used very selective 30-ms editing pulses for improved suppression of coedited MMs.Simulation and in vivo experiments confirmed excellent MM suppression, insensitive to the range of B0 frequency drifts typically encountered in vivo. Both intersubject and intrasubject studies showed that MMs, when suppressed by the improved MEGA-SPECIAL method, contributed approximately 40% to the corresponding MEGA-PRESS measurements. From the intersubject study, the coefficient of variation for GABA+/Cre (MEGA-PRESS) was 11.2% versus 7% for GABA/Cre (improved MEGA-SPECIAL), demonstrating significantly reduced variance (P = 0.005), likely coming from coedited MMs.This improved MEGA-SPECIAL sequence provides unbiased GABA measurements with reduced variance as compared with conventional MEGA-PRESS. This approach is also relatively insensitive to the range of B0 drifts typically observed in in vivo human studies. Magn Reson Med, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

  View details for DOI 10.1002/mrm.26691

  View details for PubMedID 28370458

• C-pyruvate studies. NMR in biomedicine Datta, K., Spielman, D. M. 2017; 30 (2)

  Abstract

  Hyperpolarized (13) C MRS allows in vivo interrogation of key metabolic pathways, with pyruvate (Pyr) the substrate of choice for current clinical studies. Knowledge of the liquid-state polarization is needed for full quantitation, and asymmetry of the C2 doublet, arising from 1% naturally abundant [1,2-(13) C]Pyr in any hyperpolarized [1-(13) C]Pyr sample, has been suggested as a direct measure of in vivo C1 polarization via the use of an in vitro calibration curve. Here we show that different polarization levels can yield the same C2 -doublet asymmetry, thus limiting the utility of this metric for quantitation. Furthermore, although the time evolution of doublet asymmetry is poorly modeled using the expected dominant relaxation mechanisms of carbon-proton dipolar coupling and chemical shift anisotropy, the inclusion of a C-C dipolar coupling term can explain the observed initial evolution of the C2 doublet asymmetry beyond its expected thermal equilibrium value.

  View details for DOI 10.1002/nbm.3670

  View details for PubMedID 28004867

• Doublet asymmetry for estimating polarization in hyperpolarized C-13-pyruvate studies NMR IN BIOMEDICINE Datta, K., Spielman, D. M. 2017; 30 (2)

  Abstract

  Hyperpolarized (13) C MRS allows in vivo interrogation of key metabolic pathways, with pyruvate (Pyr) the substrate of choice for current clinical studies. Knowledge of the liquid-state polarization is needed for full quantitation, and asymmetry of the C2 doublet, arising from 1% naturally abundant [1,2-(13) C]Pyr in any hyperpolarized [1-(13) C]Pyr sample, has been suggested as a direct measure of in vivo C1 polarization via the use of an in vitro calibration curve. Here we show that different polarization levels can yield the same C2 -doublet asymmetry, thus limiting the utility of this metric for quantitation. Furthermore, although the time evolution of doublet asymmetry is poorly modeled using the expected dominant relaxation mechanisms of carbon-proton dipolar coupling and chemical shift anisotropy, the inclusion of a C-C dipolar coupling term can explain the observed initial evolution of the C2 doublet asymmetry beyond its expected thermal equilibrium value.

  View details for DOI 10.1002/nbm.3670

  View details for Web of Science ID 000397274200003

  View details for PubMedCentralID PMC5330392

• A proton MR spectroscopy study of the thalamus in twins with autism spectrum disorder. Progress in neuro-psychopharmacology & biological psychiatry Hegarty, J. P., Gu, M. n., Spielman, D. M., Cleveland, S. C., Hallmayer, J. F., Lazzeroni, L. C., Raman, M. M., Frazier, T. W., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2017

  Abstract

  Multiple lines of research have reported thalamic abnormalities in individuals with autism spectrum disorder (ASD) that are associated with social communication impairments (SCI), restricted and repetitive behaviors (RRB), or sensory processing abnormalities (SPA). Thus, the thalamus may represent a common neurobiological structure that is shared across symptom domains in ASD. Same-sex monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD underwent cognitive/behavioral evaluation and magnetic resonance imaging to assess the thalamus. Neurometabolites were measured with (1)H magnetic resonance spectroscopy (MRS) utilizing a multi-voxel PRESS sequence and were referenced to creatine+phosphocreatine (tCr). N-acetyl aspartate (NAA), a marker of neuronal integrity, was reduced in twins with ASD (n=47) compared to typically-developing (TD) controls (n=33), and this finding was confirmed in a sub-sample of co-twins discordant for ASD (n=11). NAA in the thalamus was correlated to a similar extent with SCI, RRB, and SPA, such that reduced neuronal integrity was associated with greater symptom severity. Glutamate+glutamine (Glx) was also reduced in affected versus unaffected co-twins. Additionally, NAA and Glx appeared to be primarily genetically-mediated, based on comparisons between MZ and DZ twin pairs. Thus, thalamic abnormalities may be influenced by genetic susceptibility for ASD but are likely not domain-specific.

  View details for PubMedID 28941767

• Studying GABA Neurophysiology by Simultaneous [18F]Flumazenil-Positron Emission Tomography and Magnetic Resonance Spectroscopy Fung, L., Gu, M., Leuze, C., Hjoernevik, T., Shen, B., Park, J., Flores, R., Reyes, S., Holley, D., Gandhi, H., Jung, J., Lee, B., Kim, S., Khalighi, M., Gulaka, P., Zaharchuk, G., McNab, J., Quon, A., Spielman, D., Chin, F. NATURE PUBLISHING GROUP. 2016: S209

  View details for Web of Science ID 000440365600366

• CHANGES IN ACUTE FDG-PET FOLLOWING BEVACIZUMAB ADMINISTRATION IN GLIOBLASTOMA Corbin, Z., Zaharchuk, G., Spielman, D., Recht, L. OXFORD UNIV PRESS INC. 2016: 140

  View details for Web of Science ID 000398604103098

• THALAMIC METABOLITE LEVELS AND SENSORY PROCESSING IN TWINS WITH AUTISM SPECTRUM DISORDER Hegarty, J. P., Gu, M., Spielman, D., Cleveland, S., Hallmayer, J. J., Lazzeroni, L. C., Raman, M., Monterrey, J., Frazier, T., Phillips, J. M., Reiss, A. L., Hardan, A. ELSEVIER SCIENCE INC. 2016: S102

  View details for DOI 10.1016/j.jaac.2016.09.011

  View details for Web of Science ID 000541964300345

• Real-time PET/Hyperpolarized MRS/Ultrasound Molecular Imaging Fusion for Focal Prostate Cancer Detection and Guided Biopsy Valluru, K. S., Park, J., Bachawal, S. V., Liu, C., Taviani, V., Gulaka, P. K., Saenz, Y., Felt, S. A., Vilches-Moure, J. G., Daniel, B., Cheng, Z., Spielman, D. M., Willmann, J. K. SPRINGER. 2016: S152

  View details for Web of Science ID 000391801600370

• Metabolite-selective hyperpolarized C-13 imaging using extended chemical shift displacement at 9.4 T MAGNETIC RESONANCE IMAGING Yang, S., Lee, J., Joe, E., Lee, H., Choi, Y., Park, J. M., Spielman, D., Song, H., Kim, D. 2016; 34 (4): 535-540

  Abstract

  To develop a technique for frequency-selective hyperpolarized (13)C metabolic imaging in ultra-high field strength which exploits the broad spatial chemical shift displacement in providing spectral and spatial selectivity.The spatial chemical shift displacement caused by the slice-selection gradient was utilized in acquiring metabolite-selective images. Interleaved images of different metabolites were acquired by reversing the polarity of the slice-selection gradient at every repetition time, while using a low-bandwidth radio-frequency excitation pulse to alternatingly shift the displaced excitation bands outside the imaging subject. Demonstration of this technique is presented using (1)H phantom and in vivo mouse renal hyperpolarized (13)C imaging experiments with conventional chemical shift imaging and fast low-angle shot sequences.From phantom and in vivo mouse studies, the spectral selectivity of the proposed method is readily demonstrated using results of chemical shift spectroscopic imaging, which displayed clearly delineated images of different metabolites. Imaging results using the proposed method without spectral encoding also showed effective separation while also providing high spatial resolution.This method provides a way to acquire spectrally selective hyperpolarized (13)C metabolic images in a simple implementation, and with potential ability to support combination with more elaborate readout methods for faster imaging.

  View details for DOI 10.1016/j.mri.2015.12.023

  View details for Web of Science ID 000373095800025

• Hyperpolarized (13) C-lactate to (13) C-bicarbonate ratio as a biomarker for monitoring the acute response of anti-vascular endothelial growth factor (anti-VEGF) treatment. NMR in biomedicine Park, J. M., Spielman, D. M., Josan, S., Jang, T., Merchant, M., Hurd, R. E., Mayer, D., Recht, L. D. 2016; 29 (5): 650-659

  Abstract

  Hyperpolarized [1-(13) C]pyruvate MRS provides a unique imaging opportunity to study the reaction kinetics and enzyme activities of in vivo metabolism because of its favorable imaging characteristics and critical position in the cellular metabolic pathway, where it can either be reduced to lactate (reflecting glycolysis) or converted to acetyl-coenzyme A and bicarbonate (reflecting oxidative phosphorylation). Cancer tissue metabolism is altered in such a way as to result in a relative preponderance of glycolysis relative to oxidative phosphorylation (i.e. Warburg effect). Although there is a strong theoretical basis for presuming that readjustment of the metabolic balance towards normal could alter tumor growth, a robust noninvasive in vivo tool with which to measure the balance between these two metabolic processes has yet to be developed. Until recently, hyperpolarized (13) C-pyruvate imaging studies had focused solely on [1-(13) C]lactate production because of its strong signal. However, without a concomitant measure of pyruvate entry into the mitochondria, the lactate signal provides no information on the balance between the glycolytic and oxidative metabolic pathways. Consistent measurement of (13) C-bicarbonate in cancer tissue, which does provide such information, has proven difficult, however. In this study, we report the reliable measurement of (13) C-bicarbonate production in both the healthy brain and a highly glycolytic experimental glioblastoma model using an optimized (13) C MRS imaging protocol. With the capacity to obtain signal in all tumors, we also confirm for the first time that the ratio of (13) C-lactate to (13) C-bicarbonate provides a more robust metric relative to (13) C-lactate for the assessment of the metabolic effects of anti-angiogenic therapy. Our data suggest a potential application of this ratio as an early biomarker to assess therapeutic effectiveness. Furthermore, although further study is needed, the results suggest that anti-angiogenic treatment results in a rapid normalization in the relative tissue utilization of glycolytic and oxidative phosphorylation by tumor tissue. Copyright © 2016 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/nbm.3509

  View details for PubMedID 26990457

• Adipose Cell Size and Regional Fat Deposition as Predictors of Metabolic Response to Overfeeding in Insulin-Resistant and Insulin-Sensitive Humans DIABETES McLaughlin, T., Craig, C., Liu, L., Perelman, D., Allister, C., Spielman, D., Cushman, S. W. 2016; 65 (5): 1245-1254

  Abstract

  Obesity is associated with insulin resistance (IR), but significant variability exists between similarly-obese individuals, pointing to qualitative characteristics of body fat as potential mediators. To test the hypothesis that obese, insulin-sensitive (IS) individuals possess adaptive adipose cell/tissue responses, we measured subcutaneous adipose cell size, insulin-suppression-of lipolysis, and regional fat responses to short-term overfeeding in BMI-matched overweight/obese individuals classified as IS or IR. At baseline, IR subjects exhibited significantly-greater visceral adipose tissue(VAT), intrahepatic lipid(IHL), plasma FFAs , adipose cell diameter, and %small adipose cells. With weight gain (3.1+1.4 kg), IR subjects demonstrated no significant change in adipose cell size, VAT, or insulin-suppression-of lipolysis, and only 8% worsening of insulin-mediated glucose uptake (IMGU).Alternatively, IS subjects demonstrated significant adipose cell enlargement, decrease in %small adipose cells, increase in VAT, IHL, lipolysis, 45% worsening of IMGU, and decreased expression of lipid metabolism genes. Smaller baseline adipose cell size and greater enlargement with weight gain predicted decline in IMGU, as did increase in IHL, VAT, and decrease in insulin-suppression-of lipolysis. Weight gain in IS humans causes maladaptive changes in adipose cells, regional fat distribution, and insulin resistance. The correlation between worsening insulin resistance and changes in adipose cell size, VAT, IHL, and insulin-suppression-of lipolysis highlight these factors as potential mediators between obesity and insulin resistance.

  View details for DOI 10.2337/db15-1213

  View details for Web of Science ID 000375028000015

  View details for PubMedID 26884438

• Volumetric spiral chemical shift imaging of hyperpolarized [2-(13) c]pyruvate in a rat c6 glioma model. Magnetic resonance in medicine Park, J. M., Josan, S., Jang, T., Merchant, M., Watkins, R., Hurd, R. E., Recht, L. D., Mayer, D., Spielman, D. M. 2016; 75 (3): 973-984

  Abstract

  MRS of hyperpolarized [2-(13) C]pyruvate can be used to assess multiple metabolic pathways within mitochondria as the (13) C label is not lost with the conversion of pyruvate to acetyl-CoA. This study presents the first MR spectroscopic imaging of hyperpolarized [2-(13) C]pyruvate in glioma-bearing brain.Spiral chemical shift imaging with spectrally undersampling scheme (1042 Hz) and a hard-pulse excitation was exploited to simultaneously image [2-(13) C]pyruvate, [2-(13) C]lactate, and [5-(13) C]glutamate, the metabolites known to be produced in brain after an injection of hyperpolarized [2-(13) C]pyruvate, without chemical shift displacement artifacts. A separate undersampling scheme (890 Hz) was also used to image [1-(13) C]acetyl-carnitine. Healthy and C6 glioma-implanted rat brains were imaged at baseline and after dichloroacetate administration, a drug that modulates pyruvate dehydrogenase kinase activity.The baseline metabolite maps showed higher lactate and lower glutamate in tumor as compared to normal-appearing brain. Dichloroacetate led to an increase in glutamate in both tumor and normal-appearing brain. Dichloroacetate-induced %-decrease of lactate/glutamate was comparable to the lactate/bicarbonate decrease from hyperpolarized [1-(13) C]pyruvate studies. Acetyl-carnitine was observed in the muscle/fat tissue surrounding the brain.Robust volumetric imaging with hyperpolarized [2-(13) C]pyruvate and downstream products was performed in glioma-bearing rat brains, demonstrating changes in mitochondrial metabolism with dichloroacetate. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/mrm.25766

  View details for PubMedID 25946547

• Metabolite-selective hyperpolarized (13)C imaging using extended chemical shift displacement at 9.4T. Magnetic resonance imaging Yang, S., Lee, J., Joe, E., Lee, H., Choi, Y. S., Park, J. M., Spielman, D., Song, H. T., Kim, D. H. 2015

  Abstract

  To develop a technique for frequency-selective hyperpolarized (13)C metabolic imaging in ultra-high field strength which exploits the broad spatial chemical shift displacement in providing spectral and spatial selectivity.The spatial chemical shift displacement caused by the slice-selection gradient was utilized in acquiring metabolite-selective images. Interleaved images of different metabolites were acquired by reversing the polarity of the slice-selection gradient at every repetition time, while using a low-bandwidth radio-frequency excitation pulse to alternatingly shift the displaced excitation bands outside the imaging subject. Demonstration of this technique is presented using (1)H phantom and in vivo mouse renal hyperpolarized (13)C imaging experiments with conventional chemical shift imaging and fast low-angle shot sequences.From phantom and in vivo mouse studies, the spectral selectivity of the proposed method is readily demonstrated using results of chemical shift spectroscopic imaging, which displayed clearly delineated images of different metabolites. Imaging results using the proposed method without spectral encoding also showed effective separation while also providing high spatial resolution.This method provides a way to acquire spectrally selective hyperpolarized (13)C metabolic images in a simple implementation, and with potential ability to support combination with more elaborate readout methods for faster imaging.

  View details for DOI 10.1016/j.mri.2015.12.023

  View details for PubMedID 26707851

• Assessing inflammatory liver injury in an acute CCl4 model using dynamic 3D metabolic imaging of hyperpolarized [1-C-13]pyruvate NMR IN BIOMEDICINE Josan, S., Billingsley, K., Orduna, J., Park, J. M., Luong, R., Yu, L., Hurd, R., Pfefferbaum, A., Spielman, D., Mayer, D. 2015; 28 (12): 1671-1677

  Abstract

  To facilitate diagnosis and staging of liver disease, sensitive and non-invasive methods for the measurement of liver metabolism are needed. This study used hyperpolarized (13) C-pyruvate to assess metabolic parameters in a CCl4 model of liver damage in rats. Dynamic 3D (13) C chemical shift imaging data from a volume covering kidney and liver were acquired from 8 control and 10 CCl4 -treated rats. At 12 time points at 5 s temporal resolution, we quantified the signal intensities and established time courses for pyruvate, alanine, and lactate. These measurements were compared with standard liver histology and an alanine transaminase (ALT) enzyme assay using liver tissue from the same animals. All CCl4 -treated but none of the control animals showed histological liver damage and elevated ALT enzyme levels. In agreement with these results, metabolic imaging revealed an increased alanine/pyruvate ratio in liver of CCl4 -treated rats, which is indicative of elevated ALT activity. Similarly, lactate/pyruvate ratios were higher in CCl4 -treated compared with control animals, demonstrating the presence of inflammation. No significant differences in metabolite ratios were observed in kidney or vasculature. Thus this work shows that metabolic imaging using (13) C-pyruvate can be a successful tool to non-invasively assess liver damage in vivo. Copyright © 2015 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/nbm.3431

  View details for Web of Science ID 000367315100007

• Multivendor implementation and comparison of volumetric whole-brain echo-planar MR spectroscopic imaging MAGNETIC RESONANCE IN MEDICINE Sabati, M., Sheriff, S., Gu, M., Wei, J., Zhu, H., Barker, P. B., Spielman, D. M., Alger, J. R., Maudsley, A. A. 2015; 74 (5): 1209-1220

  Abstract

  To assess volumetric proton MR spectroscopic imaging (MRSI) of the human brain on multivendor MRI instruments.Echo-planar spectroscopic imaging was developed on instruments from three manufacturers, with matched specifications and acquisition protocols that accounted for differences in sampling performance, radiofrequency (RF) power, and data formats. Intersite reproducibility was evaluated for signal-normalized maps of N-acetylaspartate (NAA), creatine (Cre), and choline using phantom and human subject measurements. Comparative analyses included metrics for spectral quality, spatial coverage, and mean values in atlas-registered brain regions.Intersite differences for phantom measurements were less than 1.7% for individual metabolites and less than 0.2% for ratio measurements. Spatial uniformity ranged from 79% to 91%. The human studies found differences of mean values in the temporal lobe, but good agreement in other white matter regions, with maximum differences relative to their mean of under 3.2%. For NAA/Cre, the maximum difference was 1.8%. In gray matter, a significant difference was observed for frontal lobe NAA. Primary causes of intersite differences were attributed to shim quality, B0 drift, and accuracy of RF excitation. Correlation coefficients for measurements at each site were over 0.60, indicating good reliability.A volumetric intensity-normalized MRSI acquisition can be implemented in a comparable manner across multivendor MR instruments.

  View details for DOI 10.1002/mrm.25510

  View details for Web of Science ID 000364215900003

  View details for PubMedID 25354190

  View details for PubMedCentralID PMC4414683

• Assessing inflammatory liver injury in an acute CCl4 model using dynamic 3D metabolic imaging of hyperpolarized [1-(13) C]pyruvate. NMR in biomedicine Josan, S., Billingsley, K., Orduna, J., Park, J. M., Luong, R., Yu, L., Hurd, R., Pfefferbaum, A., Spielman, D., Mayer, D. 2015

  Abstract

  To facilitate diagnosis and staging of liver disease, sensitive and non-invasive methods for the measurement of liver metabolism are needed. This study used hyperpolarized (13) C-pyruvate to assess metabolic parameters in a CCl4 model of liver damage in rats. Dynamic 3D (13) C chemical shift imaging data from a volume covering kidney and liver were acquired from 8 control and 10 CCl4 -treated rats. At 12 time points at 5 s temporal resolution, we quantified the signal intensities and established time courses for pyruvate, alanine, and lactate. These measurements were compared with standard liver histology and an alanine transaminase (ALT) enzyme assay using liver tissue from the same animals. All CCl4 -treated but none of the control animals showed histological liver damage and elevated ALT enzyme levels. In agreement with these results, metabolic imaging revealed an increased alanine/pyruvate ratio in liver of CCl4 -treated rats, which is indicative of elevated ALT activity. Similarly, lactate/pyruvate ratios were higher in CCl4 -treated compared with control animals, demonstrating the presence of inflammation. No significant differences in metabolite ratios were observed in kidney or vasculature. Thus this work shows that metabolic imaging using (13) C-pyruvate can be a successful tool to non-invasively assess liver damage in vivo. Copyright © 2015 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/nbm.3431

  View details for PubMedID 26474216

• Hyperpolarized 13C NMR observation of lactate kinetics in skeletal muscle. journal of experimental biology Park, J. M., Josan, S., Mayer, D., Hurd, R. E., Chung, Y., Bendahan, D., Spielman, D. M., Jue, T. 2015; 218: 3308-3318

  Abstract

  The production of glycolytic end products, such as lactate, usually evokes the concept of a cellular shift from aerobic to anaerobic ATP generation and O2 insufficiency. In the classical view, muscle lactate must export to liver for clearance. Studies, however, indicate that lactate also forms under well-oxygenated conditions and have led investigators to postulate lactate shuttling from non-oxidative to oxidative muscle fiber, where it can serve as a precursor. Indeed, the intracellular lactate shuttle and the glycogen shunt hypotheses expand the vision to include a dynamic mobilization and utilization of lactate during a muscle contraction cycle. Testing the tenability of these provocative ideas during a rapid contraction cycle has posed a technical challenge. The present study herein reports the use of hyperpolarized [1-(13)C]lactate and [2-(13)C]pyruvate in dynamic nuclear polarization (DNP) NMR experiments to measure the rapid pyruvate and lactate kinetics in rat muscle. With a 2-s temporal resolution, (13)C DNP NMR detects both [1-(13)C]lactate and [2-(13)C]pyruvate kinetics in muscle. Infusing dichloroacetate to stimulate pyruvate dehydrogenase activity and shifts the kinetics toward oxidative metabolism. Bicarbonate formation increases sharply from [1-(13)C]lactate. Acetyl-L-carnitine, acetoacetate, and glutamate levels rise. Such a quick mobilization of pyruvate and lactate toward oxidative metabolism supports the postulated role of lactate in the glycogen shunt and the intracellular lactate shuttle models. The study introduces then an innovative DNP approach to measure metabolite transients, which will help delineate the cellular and physiological role of lactate and glycolytic end products.

  View details for DOI 10.1242/jeb.123141

  View details for PubMedID 26347554

• Association of Metabolite Concentrations and Water Diffusivity in Normal Appearing Brain Tissue with Glioma Grade JOURNAL OF NEUROIMAGING Maudsley, A. A., Roy, B., Gupta, R. K., Sheriff, S., Awasthi, R., Gu, M., Husain, N., Mohakud, S., Behari, S., Spielman, D. M. 2014; 24 (6): 585-589

  Abstract

  Studies of brain tumors have identified altered tissue metabolism and water diffusion in MRI normal appearing tissue regions. In this retrospective study the relationship of these imaging measures with tumor grade in gliomas was investigated.MR spectroscopic imaging of whole brain and mean diffusivity (MD) measurements were obtained in subjects with untreated glioma and from normal control subjects. Mean metabolite values for N-acetylaspartate (NAA), total creatine (Cre), and total choline (Cho) were obtained in gray- and white-matter regions for the hemisphere contralateral to the tumor location, and MD values were obtained from contralateral normal-appearing white matter. Analyses tested for differences in mean values between subject groups while accounting for age.Analysis demonstrated increased NAA/Cre and MD, and decreased Cho/NAA for all tumor grades relative to control values. Differences between tumor grades were also observed for NAA, NAA/Cre, and Cho/NAA. Abnormal values of water diffusion were also observed, but with only a weak association between alterations in diffusion and tissue metabolites.This study supports previous observations of altered tissue metabolism and water diffusion in normal-appearing white matter while additionally finding differences of metabolite values in gray matter and an association with tumor grade.

  View details for DOI 10.1111/jon.12063

  View details for Web of Science ID 000344354600008

  View details for PubMedCentralID PMC4874645

• The feasibility of assessing branched-chain amino acid metabolism in cellular models of prostate cancer with hyperpolarized [1-(13)C]-ketoisocaproate. Magnetic resonance imaging Billingsley, K. L., Park, J. M., Josan, S., Hurd, R., Mayer, D., Spielman-Sun, E., Nishimura, D. G., Brooks, J. D., Spielman, D. 2014; 32 (7): 791-795

  Abstract

  Recent advancements in the field of hyperpolarized (13)C magnetic resonance spectroscopy (MRS) have yielded powerful techniques capable of real-time analysis of metabolic pathways. These non-invasive methods have increasingly shown application in impacting disease diagnosis and have further been employed in mechanistic studies of disease onset and progression. Our goals were to investigate branched-chain aminotransferase (BCAT) activity in prostate cancer with a novel molecular probe, hyperpolarized [1-(13)C]-2-ketoisocaproate ([1-(13)C]-KIC), and explore the potential of branched-chain amino acid (BCAA) metabolism to serve as a biomarker. Using traditional spectrophotometric assays, BCAT enzymatic activities were determined in vitro for various sources of prostate cancer (human, transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse and human cell lines). These preliminary studies indicated that low levels of BCAT activity were present in all models of prostate cancer but enzymatic levels are altered significantly in prostate cancer relative to healthy tissue. The MR spectroscopic studies were conducted with two cellular models (PC-3 and DU-145) that exhibited levels of BCAA metabolism comparable to the human disease state. Hyperpolarized [1-(13)C]-KIC was administered to prostate cancer cell lines, and the conversion of [1-(13)C]-KIC to the metabolic product, [1-(13)C]-leucine ([1-(13)C]-Leu), could be monitored via hyperpolarized (13)C MRS.

  View details for DOI 10.1016/j.mri.2014.04.015

  View details for PubMedID 24907854

  View details for PubMedCentralID PMC4099288

• The feasibility of assessing branched-chain amino acid metabolism in cellular models of prostate cancer with hyperpolarized [1-C-13]-ketoisocaproate MAGNETIC RESONANCE IMAGING Billingsley, K. L., Park, J., Josan, S., Hurd, R., Mayer, D., Spielman-Sun, E., Nishimura, D. G., Brooks, J. D., Spielman, D. 2014; 32 (7): 791–95

  View details for DOI 10.1016/j.mri.2014.04.015

  View details for Web of Science ID 000339531900001

• Dynamic metabolic imaging of hyperpolarized [2-(13) C]pyruvate using spiral chemical shift imaging with alternating spectral band excitation. Magnetic resonance in medicine Josan, S., Hurd, R., Park, J. M., Yen, Y., Watkins, R., Pfefferbaum, A., Spielman, D., Mayer, D. 2014; 71 (6): 2051-2058

  Abstract

  In contrast to [1-(13) C]pyruvate, hyperpolarized [2-(13) C]pyruvate permits the ability to follow the (13) C label beyond flux through pyruvate dehydrogenase complex and investigate the incorporation of acetyl-coenzyme A into different metabolic pathways. However, chemical shift imaging (CSI) with [2-(13) C]pyruvate is challenging owing to the large spectral dispersion of the resonances, which also leads to severe chemical shift displacement artifacts for slice-selective acquisitions.This study introduces a sequence for three-dimensional CSI of [2-(13) C]pyruvate using spectrally selective excitation of limited frequency bands containing a subset of metabolites. Dynamic CSI data were acquired alternately from multiple frequency bands in phantoms for sequence testing and in vivo in rat heart.Phantom experiments verified the radiofrequency pulse design and demonstrated that the signal behavior of each group of resonances was unaffected by excitation of the other frequency bands. Dynamic three-dimensional (13) C CSI data demonstrated the sequence capability to image pyruvate, lactate, acetylcarnitine, glutamate, and acetoacetate, enabling the analysis of organ-specific spectra and metabolite time courses.The presented method allows CSI of widely separated resonances without chemical shift displacement artifact, acquiring multiple frequency bands alternately to obtain dynamic time-course information. This approach enables robust imaging of downstream metabolic products of acetyl-coenzyme A with hyperpolarized [2-(13) C]pyruvate. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.

  View details for DOI 10.1002/mrm.24871

  View details for PubMedID 23878057

• Hyperpolarized [1,4-C-13]-diethylsuccinate: a potential DNP substrate for in vivo metabolic imaging NMR IN BIOMEDICINE Billingsley, K. L., Josan, S., Park, J. M., Tee, S. S., Spielman-Sun, E., Hurd, R., Mayer, D., Spielman, D. 2014; 27 (3): 356-362

  Abstract

  The tricarboxylic acid (TCA) cycle performs an essential role in the regulation of energy and metabolism, and deficiencies in this pathway are commonly correlated with various diseases. However, the development of non-invasive techniques for the assessment of the cycle in vivo has remained challenging. In this work, the applicability of a novel imaging agent, [1,4-(13) C]-diethylsuccinate, for hyperpolarized (13) C metabolic imaging of the TCA cycle was explored. In vivo spectroscopic studies were conducted in conjunction with in vitro analyses to determine the metabolic fate of the imaging agent. Contrary to previous reports (Zacharias NM et al. J. Am. Chem. Soc. 2012; 134: 934-943), [(13) C]-labeled diethylsuccinate was primarily metabolized to succinate-derived products not originating from TCA cycle metabolism. These results illustrate potential issues of utilizing dialkyl ester analogs of TCA cycle intermediates as molecular probes for hyperpolarized (13) C metabolic imaging. Copyright © 2014 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/nbm.3071

  View details for Web of Science ID 000330798100013

  View details for PubMedID 24421249

• Improved Slice-Selective Adiabatic Excitation MAGNETIC RESONANCE IN MEDICINE Balchandani, P., Glover, G., Pauly, J., Spielman, D. 2014; 71 (1): 75-82

  Abstract

  PURPOSE: The purpose of this work is to design an improved Slice-selective Tunable-flip AdiaBatic Low peak-power Excitation (STABLE) pulse with shorter duration and increased off-resonance immunity to make it suitable for use in a greater range of applications and at higher field strengths. An additional aim is to design a variant of this pulse to achieve B(1) -insensitive, fat-suppressed excitation. METHODS: The adiabatic SLR algorithm was used to generate a more uniform spectral pulse envelope for this improved radiofrequency pulse for adiabatic slice-selective excitation, called STABLE-2. Pulse parameters were adjusted to design a version of STABLE-2 with a spectral null centered on lipids. RESULTS: In vivo images obtained of the human brain at 3 and 7 T demonstrate that STABLE-2 provides robust, uniform, slice-selective excitation over a range of B(1) values. Phantom and in vivo knee images obtained at 3 T demonstrate the effectiveness of STABLE-2 for fat suppression. CONCLUSIONS: STABLE-2 achieves B(1) -insensitive slice-selective excitation while providing greater off-resonance immunity and a shorter pulse duration, when compared to the original STABLE pulse. In particular, the 9.8-ms STABLE-2 pulse provides slice selectivity over 120 Hz whereas the 21-ms STABLE pulse is limited to 80 Hz off-resonance. B(1) -Insensitive fat-suppressed excitation may also be achieved by using a variant of this pulse. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.

  View details for DOI 10.1002/mrm.24630

  View details for Web of Science ID 000328580300010

  View details for PubMedID 23401184

• In vivo investigation of cardiac metabolism in the rat using MRS of hyperpolarized [1-(13) C] and [2-(13) C]pyruvate. NMR in biomedicine Josan, S., Park, J. M., Hurd, R., Yen, Y., Pfefferbaum, A., Spielman, D., Mayer, D. 2013; 26 (12): 1680-1687

  Abstract

  Hyperpolarized (13) C MRS allows the in vivo assessment of pyruvate dehydrogenase complex (PDC) flux, which converts pyruvate to acetyl-coenzyme A (acetyl-CoA). [1-(13) C]pyruvate has been used to measure changes in cardiac PDC flux, with demonstrated increase in (13) C-bicarbonate production after dichloroacetate (DCA) administration. With [1-(13) C]pyruvate, the (13) C label is released as (13) CO2 /(13) C-bicarbonate, and, hence, does not allow us to follow the fate of acetyl-CoA. Pyruvate labeled in the C2 position has been used to track the (13) C label into the TCA (tricarboxylic acid) cycle and measure [5-(13) C]glutamate as well as study changes in [1-(13) C]acetylcarnitine with DCA and dobutamine. This work investigates changes in the metabolic fate of acetyl-CoA in response to metabolic interventions of DCA-induced increased PDC flux in the fed and fasted state, and increased cardiac workload with dobutamine in vivo in rat heart at two different pyruvate doses. DCA led to a modest increase in the (13) C labeling of [5-(13) C]glutamate, and a considerable increase in [1-(13) C]acetylcarnitine and [1,3-(13) C]acetoacetate peaks. Dobutamine resulted in an increased labeling of [2-(13) C]lactate, [2-(13) C]alanine and [5-(13) C]glutamate. The change in glutamate with dobutamine was observed using a high pyruvate dose but not with a low dose. The relative changes in the different metabolic products provide information about the relationship between PDC-mediated oxidation of pyruvate and its subsequent incorporation into the TCA cycle compared with other metabolic pathways. Using a high dose of pyruvate may provide an improved ability to observe changes in glutamate. Copyright © 2013 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/nbm.3003

  View details for PubMedID 23904148

  View details for PubMedCentralID PMC3838505

• Prospective neurochemical characterization of child offspring of parents with bipolar disorder. Psychiatry research Singh, M. K., Jo, B., Adleman, N. E., Howe, M., Bararpour, L., Kelley, R. G., Spielman, D., Chang, K. D. 2013; 214 (2): 153-160

  Abstract

  We wished to determine whether decreases in N-acetyl aspartate (NAA) and increases in myoinositol (mI) concentrations as a ratio of creatine (Cr) occurred in the dorsolateral prefrontal cortex (DLPFC) of pediatric offspring of parents with bipolar disorder (BD) and a healthy comparison group (HC) over a 5-year period using proton magnetic resonance spectroscopy ((1)H-MRS). Paticipants comprised 64 offspring (9-18 years old) of parents with BD (36 with established BD, and 28 offspring with symptoms subsyndromal to mania) and 28 HCs, who were examined for group differences in NAA/Cr and mI/Cr in the DLPFC at baseline and follow-up at either 8, 10, 12, 52, 104, 156, 208, or 260 weeks. No significant group differences were found in metabolite concentrations at baseline or over time. At baseline, BD offspring had trends for higher mI/Cr concentrations in the right DLPFC than the HC group. mI/Cr concentrations increased with age, but no statistically significant group differences were found between groups on follow-up. It may be the case that with intervention youth at risk for BD are normalizing otherwise potentially aberrant neurochemical trajectories in the DLPFC. A longer period of follow-up may be required before observing any group differences.

  View details for DOI 10.1016/j.pscychresns.2013.05.005

  View details for PubMedID 24028795

• Prospective neurochemical characterization of child offspring of parents with bipolar disorder PSYCHIATRY RESEARCH-NEUROIMAGING Singh, M. K., Jo, B., Adleman, N. E., Howe, M., Bararpour, L., Kelley, R. G., Spielman, D., Chang, K. D. 2013; 214 (2): 153-160

  Abstract

  We wished to determine whether decreases in N-acetyl aspartate (NAA) and increases in myoinositol (mI) concentrations as a ratio of creatine (Cr) occurred in the dorsolateral prefrontal cortex (DLPFC) of pediatric offspring of parents with bipolar disorder (BD) and a healthy comparison group (HC) over a 5-year period using proton magnetic resonance spectroscopy ((1)H-MRS). Paticipants comprised 64 offspring (9-18 years old) of parents with BD (36 with established BD, and 28 offspring with symptoms subsyndromal to mania) and 28 HCs, who were examined for group differences in NAA/Cr and mI/Cr in the DLPFC at baseline and follow-up at either 8, 10, 12, 52, 104, 156, 208, or 260 weeks. No significant group differences were found in metabolite concentrations at baseline or over time. At baseline, BD offspring had trends for higher mI/Cr concentrations in the right DLPFC than the HC group. mI/Cr concentrations increased with age, but no statistically significant group differences were found between groups on follow-up. It may be the case that with intervention youth at risk for BD are normalizing otherwise potentially aberrant neurochemical trajectories in the DLPFC. A longer period of follow-up may be required before observing any group differences.

  View details for DOI 10.1016/j.pscychresns.2013.05.005

  View details for Web of Science ID 000325432300009

  View details for PubMedID 24028795

  View details for PubMedCentralID PMC3796054

• Association of metabolite concentrations and water diffusivity in normal appearing brain tissue with glioma grade. Journal of neuroimaging : official journal of the American Society of Neuroimaging Maudsley, A. A., Roy, B., Gupta, R. K., Sheriff, S., Awasthi, R., Gu, M., Husain, N., Mohakud, S., Behari, S., Spielman, D. M. 2013; 24 (6): 585-589

  Abstract

  Studies of brain tumors have identified altered tissue metabolism and water diffusion in MRI normal appearing tissue regions. In this retrospective study the relationship of these imaging measures with tumor grade in gliomas was investigated.MR spectroscopic imaging of whole brain and mean diffusivity (MD) measurements were obtained in subjects with untreated glioma and from normal control subjects. Mean metabolite values for N-acetylaspartate (NAA), total creatine (Cre), and total choline (Cho) were obtained in gray- and white-matter regions for the hemisphere contralateral to the tumor location, and MD values were obtained from contralateral normal-appearing white matter. Analyses tested for differences in mean values between subject groups while accounting for age.Analysis demonstrated increased NAA/Cre and MD, and decreased Cho/NAA for all tumor grades relative to control values. Differences between tumor grades were also observed for NAA, NAA/Cre, and Cho/NAA. Abnormal values of water diffusion were also observed, but with only a weak association between alterations in diffusion and tissue metabolites.This study supports previous observations of altered tissue metabolism and water diffusion in normal-appearing white matter while additionally finding differences of metabolite values in gray matter and an association with tumor grade.

  View details for DOI 10.1111/jon.12063

  View details for PubMedID 24251857

  View details for PubMedCentralID PMC4874645

• PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxyglucose. Tee, S., Park, J., Spielman, D. AMER ASSOC CANCER RESEARCH. 2013

  View details for DOI 10.1158/1535-7163.TARG-13-C156

  View details for Web of Science ID 000209496800587

• Exchange-linked dissolution agents in dissolution-DNP (13)C metabolic imaging. Magnetic resonance in medicine Hurd, R. E., Spielman, D., Josan, S., Yen, Y., Pfefferbaum, A., Mayer, D. 2013; 70 (4): 936-942

  Abstract

  PURPOSE: The use of unlabeled exchange-linked dissolution agents in hyperpolarized metabolic imaging was studied to examine pool size limits and saturation relative to the availability of NADH. METHODS: Three-dimensional dynamic metabolic images were obtained, and compared following injection of a bolus of hyperpolarized [1-(13) C]pyruvate, prepared with and without unlabeled sodium lactate in the dissolution buffer. Comparisons were made on the basis of apparent rate constants and [1-(13) C]lactate signal-to-noise ratio. Range finding data were obtained for different bolus compositions. Isotope exchange was also probed in the reverse direction, following injection of a bolus of hyperpolarized [1-(13) C]lactate, with and without unlabeled sodium pyruvate in the dissolution buffer. RESULTS: Liver, kidney, and vascular regions of interest all showed an increase in [1-(13) C]lactate signal with addition of unlabeled sodium lactate in the dissolution buffer. Injection of hyperpolarized [1-(13) C]lactate with unlabeled sodium pyruvate in the dissolution buffer, provided exchange rate constants K(lp) for kidney and vascular regions of interest. CONCLUSIONS: These results are consistent with a high level of (13) C-exchange, and with labeling rates that are limited by steady-state pool sizes in vivo. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.

  View details for DOI 10.1002/mrm.24544

  View details for PubMedID 23165935

  View details for PubMedCentralID PMC3660543

• Effects of Isoflurane Anesthesia on Hyperpolarized C-13 Metabolic Measurements in Rat Brain MAGNETIC RESONANCE IN MEDICINE Josan, S., Hurd, R., Billingsley, K., Senadheera, L., Park, J. M., Yen, Y., Pfefferbaum, A., Spielman, D., Mayer, D. 2013; 70 (4): 1117-1124

  Abstract

  PURPOSE: Commonly used anesthetic agents such as isoflurane are known to be potent cerebral vasodilators, with reported dose-dependent increase in cerebral blood flow and cerebral blood volume. Despite the widespread use of isoflurane in hyperpolarized (13) C preclinical research studies, a quantitative assessment of its effect on metabolic measurements is limited. This work investigates the effect of isoflurane anesthesia dose on hyperpolarized (13) C MR metabolic measurements in rat brain for [1-(13) C]pyruvate and 2-keto[1-(13) C]isocaproate. METHODS: Dynamic 2D and 3D spiral chemical shift imaging was used to acquire metabolic images of rat brain as well as kidney and liver following bolus injections of hyperpolarized [1-(13) C]pyruvate or 2-keto[1-(13) C]isocaproate. The impact of a "low dose" vs. a "high dose" of isoflurane on cerebral metabolite levels and apparent conversion rates was examined. RESULTS: The cerebral substrate signal levels, and hence the metabolite-to-substrate ratios and apparent conversion rates, were found to depend markedly on isoflurane dose, while signal levels of metabolic products and their ratios, e.g. bicarbonate/lactate, were largely insensitive to isoflurane levels. No obvious dependence on isoflurane was observed in kidney or liver for pyruvate. CONCLUSION: This study highlights the importance of careful attention to the effects of anesthesia on the metabolic measures for hyperpolarized (13) C metabolic imaging in brain. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.

  View details for DOI 10.1002/mrm.24532

  View details for Web of Science ID 000325136300023

• Exchange-Linked Dissolution Agents in Dissolution-DNP C-13 Metabolic Imaging MAGNETIC RESONANCE IN MEDICINE Hurd, R. E., Spielman, D., Josan, S., Yen, Y., Pfefferbaum, A., Mayer, D. 2013; 70 (4): 936-942

  Abstract

  PURPOSE: The use of unlabeled exchange-linked dissolution agents in hyperpolarized metabolic imaging was studied to examine pool size limits and saturation relative to the availability of NADH. METHODS: Three-dimensional dynamic metabolic images were obtained, and compared following injection of a bolus of hyperpolarized [1-(13) C]pyruvate, prepared with and without unlabeled sodium lactate in the dissolution buffer. Comparisons were made on the basis of apparent rate constants and [1-(13) C]lactate signal-to-noise ratio. Range finding data were obtained for different bolus compositions. Isotope exchange was also probed in the reverse direction, following injection of a bolus of hyperpolarized [1-(13) C]lactate, with and without unlabeled sodium pyruvate in the dissolution buffer. RESULTS: Liver, kidney, and vascular regions of interest all showed an increase in [1-(13) C]lactate signal with addition of unlabeled sodium lactate in the dissolution buffer. Injection of hyperpolarized [1-(13) C]lactate with unlabeled sodium pyruvate in the dissolution buffer, provided exchange rate constants K(lp) for kidney and vascular regions of interest. CONCLUSIONS: These results are consistent with a high level of (13) C-exchange, and with labeling rates that are limited by steady-state pool sizes in vivo. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.

  View details for DOI 10.1002/mrm.24544

  View details for Web of Science ID 000325136300005

  View details for PubMedCentralID PMC3660543

• Measuring mitochondrial metabolism in rat brain in vivo using MR Spectroscopy of hyperpolarized [2-(13) C]pyruvate. NMR in biomedicine Park, J. M., Josan, S., Grafendorfer, T., Yen, Y., Hurd, R. E., Spielman, D. M., Mayer, D. 2013; 26 (10): 1197-1203

  Abstract

  Hyperpolarized [1-(13) C]pyruvate ([1-(13) C]Pyr) has been used to assess metabolism in healthy and diseased states, focusing on the downstream labeling of lactate (Lac), bicarbonate and alanine. Although hyperpolarized [2-(13) C]Pyr, which retains the labeled carbon when Pyr is converted to acetyl-coenzyme A, has been used successfully to assess mitochondrial metabolism in the heart, the application of [2-(13) C]Pyr in the study of brain metabolism has been limited to date, with Lac being the only downstream metabolic product reported previously. In this study, single-time-point chemical shift imaging data were acquired from rat brain in vivo. [5-(13) C]Glutamate, [1-(13) C]acetylcarnitine and [1-(13) C]citrate were detected in addition to resonances from [2-(13) C]Pyr and [2-(13) C]Lac. Brain metabolism was further investigated by infusing dichloroacetate, which upregulates Pyr flux to acetyl-coenzyme A. After dichloroacetate administration, a 40% increase in [5-(13) C]glutamate from 0.014 ± 0.004 to 0.020 ± 0.006 (p = 0.02), primarily from brain, and a trend to higher citrate (0.002 ± 0.001 to 0.004 ± 0.002) were detected, whereas [1-(13) C]acetylcarnitine was increased in peripheral tissues. This study demonstrates, for the first time, that hyperpolarized [2-(13) C]Pyr can be used for the in vivo investigation of mitochondrial function and tricarboxylic acid cycle metabolism in brain. Copyright © 2013 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/nbm.2935

  View details for PubMedID 23553852

• Effects of isoflurane anesthesia on hyperpolarized (13)C metabolic measurements in rat brain. Magnetic resonance in medicine Josan, S., Hurd, R., Billingsley, K., Senadheera, L., Park, J. M., Yen, Y., Pfefferbaum, A., Spielman, D., Mayer, D. 2013; 70 (4): 1117-1124

  Abstract

  PURPOSE: Commonly used anesthetic agents such as isoflurane are known to be potent cerebral vasodilators, with reported dose-dependent increase in cerebral blood flow and cerebral blood volume. Despite the widespread use of isoflurane in hyperpolarized (13) C preclinical research studies, a quantitative assessment of its effect on metabolic measurements is limited. This work investigates the effect of isoflurane anesthesia dose on hyperpolarized (13) C MR metabolic measurements in rat brain for [1-(13) C]pyruvate and 2-keto[1-(13) C]isocaproate. METHODS: Dynamic 2D and 3D spiral chemical shift imaging was used to acquire metabolic images of rat brain as well as kidney and liver following bolus injections of hyperpolarized [1-(13) C]pyruvate or 2-keto[1-(13) C]isocaproate. The impact of a "low dose" vs. a "high dose" of isoflurane on cerebral metabolite levels and apparent conversion rates was examined. RESULTS: The cerebral substrate signal levels, and hence the metabolite-to-substrate ratios and apparent conversion rates, were found to depend markedly on isoflurane dose, while signal levels of metabolic products and their ratios, e.g. bicarbonate/lactate, were largely insensitive to isoflurane levels. No obvious dependence on isoflurane was observed in kidney or liver for pyruvate. CONCLUSION: This study highlights the importance of careful attention to the effects of anesthesia on the metabolic measures for hyperpolarized (13) C metabolic imaging in brain. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.

  View details for DOI 10.1002/mrm.24532

  View details for PubMedID 23086864

• Aberrant basal ganglia metabolism in fragile X syndrome: a magnetic resonance spectroscopy study JOURNAL OF NEURODEVELOPMENTAL DISORDERS Bruno, J. L., Shelly, E. W., Quintin, E., Rostami, M., Patnaik, S., Spielman, D., Mayer, D., Gu, M., Lightbody, A. A., Reiss, A. L. 2013; 5

  Abstract

  The profile of cognitive and behavioral variation observed in individuals with fragile X syndrome (FXS), the most common known cause of inherited intellectual impairment, suggests aberrant functioning of specific brain systems. Research investigating animal models of FXS, characterized by limited or lack of fragile X mental retardation protein, (FMRP), has linked brain dysfunction to deficits in the cholinergic and glutamatergic systems. Thus, we sought to examine in vivo levels of neurometabolites related to cholinergic and glutamatergic functioning in males and females with FXS.The study participants included 18 adolescents and young adults with FXS, and a comparison group of 18 individuals without FXS matched for age, sex and general intellectual functioning. Proton magnetic resonance spectroscopy (MRS) was used to assess neurometabolite levels in the caudate nucleus, a region known to be greatly enlarged and involved in abnormal brain circuitry in individuals with FXS. A general linear model framework was used to compare group differences in metabolite concentration.We observed a decrease in choline (P = 0.027) and in glutamate + glutamine (P = 0.032) in the caudate nucleus of individuals with FXS, relative to individuals in the comparison group.This study provides evidence of metabolite differences in the caudate nucleus, a brain region of potential importance to our understanding of the neural deficits underlying FXS. These metabolic differences may be related to aberrant receptor signaling seen in animal models. Furthermore, identification of the specific neurometabolites involved in FXS dysfunction could provide critical biomarkers for the design and efficacy tracking of disease-specific pharmacological treatments.

  View details for DOI 10.1186/1866-1955-5-20

  View details for Web of Science ID 000324055000001

  View details for PubMedCentralID PMC3766683

• In vivo measurement of aldehyde dehydrogenase-2 activity in rat liver ethanol model using dynamic MRSI of hyperpolarized [1-(13) C]pyruvate. NMR in biomedicine Josan, S., Xu, T., Yen, Y., Hurd, R., Ferreira, J., Chen, C., Mochly-Rosen, D., Pfefferbaum, A., Mayer, D., Spielman, D. 2013; 26 (6): 607-612

  Abstract

  To date, measurements of the activity of aldehyde dehydrogenase-2 (ALDH2), a critical mitochondrial enzyme for the elimination of certain cytotoxic aldehydes in the body and a promising target for drug development, have been largely limited to in vitro methods. Recent advancements in MRS of hyperpolarized (13) C-labeled substrates have provided a method to detect and image in vivo metabolic pathways with signal-to-noise ratio gains greater than 10 000-fold over conventional MRS techniques. However aldehydes, because of their toxicity and short T1 relaxation times, are generally poor targets for such (13) C-labeled studies. In this work, we show that dynamic MRSI of hyperpolarized [1-(13) C]pyruvate and its conversion to [1-(13) C]lactate can provide an indirect in vivo measurement of ALDH2 activity via the concentration of NADH (nicotinamide adenine dinucleotide, reduced form), a co-factor common to both the reduction of pyruvate to lactate and the oxidation of acetaldehyde to acetate. Results from a rat liver ethanol model (n = 9) show that changes in (13) C-lactate labeling following the bolus injection of hyperpolarized pyruvate are highly correlated with changes in ALDH2 activity (R(2)  = 0.76). Copyright © 2012 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/nbm.2897

  View details for PubMedID 23225495

  View details for PubMedCentralID PMC3634870

• Utility of multiparametric 3-T MRI for glioma characterization. Neuroradiology Roy, B., Gupta, R. K., Maudsley, A. A., Awasthi, R., Sheriff, S., Gu, M., Husain, N., Mohakud, S., Behari, S., Pandey, C. M., Rathore, R. K., Spielman, D. M., Alger, J. R. 2013; 55 (5): 603-613

  Abstract

  Accurate grading of cerebral glioma using conventional structural imaging techniques remains challenging due to the relatively poor sensitivity and specificity of these methods. The purpose of this study was to evaluate the relative sensitivity and specificity of structural magnetic resonance imaging and MR measurements of perfusion, diffusion, and whole-brain spectroscopic parameters for glioma grading.Fifty-six patients with radiologically suspected untreated glioma were studied with T1- and T2-weighted MR imaging, dynamic contrast-enhanced MR imaging, diffusion tensor imaging, and volumetric whole-brain MR spectroscopic imaging. Receiver-operating characteristic analysis was performed using the relative cerebral blood volume (rCBV), apparent diffusion coefficient, fractional anisotropy, and multiple spectroscopic parameters to determine optimum thresholds for tumor grading and to obtain the sensitivity, specificity, and positive and negative predictive values for identifying high-grade gliomas. Logistic regression was performed to analyze all the parameters together.The rCBV individually classified glioma as low and high grade with a sensitivity and specificity of 100 and 88 %, respectively, based on a threshold value of 3.34. On combining all parameters under consideration, the classification was achieved with 2 % error and sensitivity and specificity of 100 and 96 %, respectively.Individually, CBV measurement provides the greatest diagnostic performance for predicting glioma grade; however, the most accurate classification can be achieved by combining all of the imaging parameters.

  View details for DOI 10.1007/s00234-013-1145-x

  View details for PubMedID 23377234

• Metabolic response of glioma to dichloroacetate measured in vivo by hyperpolarized C-13 magnetic resonance spectroscopic imaging NEURO-ONCOLOGY Park, J. M., Recht, L. D., Josan, S., Merchant, M., Jang, T., Yen, Y., Hurd, R. E., Spielman, D. M., Mayer, D. 2013; 15 (4): 433-441

  Abstract

  The metabolic phenotype that derives disproportionate energy via glycolysis in solid tumors, including glioma, leads to elevated lactate labeling in metabolic imaging using hyperpolarized [1-(13)C]pyruvate. Although the pyruvate dehydrogenase (PDH)-mediated flux from pyruvate to acetyl coenzyme A can be indirectly measured through the detection of carbon-13 ((13)C)-labeled bicarbonate, it has proven difficult to visualize (13)C-bicarbonate at high enough levels from injected [1-(13)C]pyruvate for quantitative analysis in brain. The aim of this study is to improve the detection of (13)C-labeled metabolites, in particular bicarbonate, in glioma and normal brain in vivo and to measure the metabolic response to dichloroacetate, which upregulates PDH activity.An optimized protocol for chemical shift imaging and high concentration of hyperpolarized [1-(13)C]pyruvate were used to improve measurements of lactate and bicarbonate in C6 glioma-transplanted rat brains. Hyperpolarized [1-(13)C]pyruvate was injected before and 45 min after dichloroacetate infusion. Metabolite ratios of lactate to bicarbonate were calculated to provide improved metrics for characterizing tumor metabolism.Glioma and normal brain were well differentiated by lactate-to-bicarbonate ratio (P = .002, n = 5) as well as bicarbonate (P = .0002) and lactate (P = .001), and a stronger response to dichloroacetate was observed in glioma than in normal brain.Our results clearly demonstrate for the first time the feasibility of quantitatively detecting (13)C-bicarbonate in tumor-bearing rat brain in vivo, permitting the measurement of dichloroacetate-modulated changes in PDH flux. The simultaneous detection of lactate and bicarbonate provides a tool for a more comprehensive analysis of glioma metabolism and the assessment of metabolic agents as anti-brain cancer drugs.

  View details for DOI 10.1093/neuonc/nos319

  View details for Web of Science ID 000316965600005

  View details for PubMedID 23328814

  View details for PubMedCentralID PMC3607261

• Quantification of glutamate and glutamine using constant-time point-resolved spectroscopy at 3 T NMR IN BIOMEDICINE Gu, M., Zahr, N. M., Spielman, D. M., Sullivan, E. V., Pfefferbaum, A., Mayer, D. 2013; 26 (2): 164-172

  Abstract

  Separate quantification of glutamate (Glu) and glutamine (Gln) using conventional MRS on clinical scanners is challenging. In previous work, constant-time point-resolved spectroscopy (CT-PRESS) was optimized at 3 T to detect Glu, but did not resolve Gln. To quantify Glu and Gln, a time-domain basis set was constructed taking into account metabolite T(2) relaxation times and dephasing from B(0) inhomogeneity. Metabolite concentrations were estimated by fitting the basis one-dimensional CT-PRESS diagonal magnitude spectra to the measured spectrum. This method was first validated using seven custom-built phantoms containing variable metabolite concentrations, and then applied to in vivo data acquired in rats exposed to vaporized ethanol and controls. Separate metabolite quantification revealed increased Gln after 16 weeks and increased Glu after 24 weeks of vaporized ethanol exposure in ethanol-treated compared with control rats. Without separate quantification, the signal from the combined resonances of Glu and Gln (Glx) showed an increase at both 16 and 24 weeks in ethanol-exposed rats, precluding the determination of the independent and differential contribution of each metabolite at each time.

  View details for DOI 10.1002/nbm.2831

  View details for Web of Science ID 000313886500007

  View details for PubMedID 22761057

• Aberrant basal ganglia metabolism in fragile X syndrome: a magnetic resonance spectroscopy study. Journal of neurodevelopmental disorders Bruno, J. L., Shelly, E. W., Quintin, E., Rostami, M., Patnaik, S., Spielman, D., Mayer, D., Gu, M., Lightbody, A. A., Reiss, A. L. 2013; 5 (1): 20-?

  Abstract

  The profile of cognitive and behavioral variation observed in individuals with fragile X syndrome (FXS), the most common known cause of inherited intellectual impairment, suggests aberrant functioning of specific brain systems. Research investigating animal models of FXS, characterized by limited or lack of fragile X mental retardation protein, (FMRP), has linked brain dysfunction to deficits in the cholinergic and glutamatergic systems. Thus, we sought to examine in vivo levels of neurometabolites related to cholinergic and glutamatergic functioning in males and females with FXS.The study participants included 18 adolescents and young adults with FXS, and a comparison group of 18 individuals without FXS matched for age, sex and general intellectual functioning. Proton magnetic resonance spectroscopy (MRS) was used to assess neurometabolite levels in the caudate nucleus, a region known to be greatly enlarged and involved in abnormal brain circuitry in individuals with FXS. A general linear model framework was used to compare group differences in metabolite concentration.We observed a decrease in choline (P = 0.027) and in glutamate + glutamine (P = 0.032) in the caudate nucleus of individuals with FXS, relative to individuals in the comparison group.This study provides evidence of metabolite differences in the caudate nucleus, a brain region of potential importance to our understanding of the neural deficits underlying FXS. These metabolic differences may be related to aberrant receptor signaling seen in animal models. Furthermore, identification of the specific neurometabolites involved in FXS dysfunction could provide critical biomarkers for the design and efficacy tracking of disease-specific pharmacological treatments.

  View details for DOI 10.1186/1866-1955-5-20

  View details for PubMedID 23981510

• Metabolite kinetics in C6 rat glioma model using magnetic resonance spectroscopic imaging of hyperpolarized [1-13C]pyruvate MAGNETIC RESONANCE IN MEDICINE Park, J. M., Josan, S., Jang, T., Merchant, M., Yen, Y., Hurd, R. E., Recht, L., Spielman, D. M., Mayer, D. 2012; 68 (6): 1886-1893

  Abstract

  In addition to an increased lactate-to-pyruvate ratio, altered metabolism of a malignant glioma can be further characterized by its kinetics. Spatially resolved dynamic data of pyruvate and lactate from C6-implanted female Sprague-Dawley rat brain were acquired using a spiral chemical shift imaging sequence after a bolus injection of a hyperpolarized [1-(13)C]pyruvate. Apparent rate constants for the conversion of pyruvate to lactate in three different regions (glioma, normal appearing brain, and vasculature) were estimated based on a two-site exchange model. The apparent conversion rate constant was 0.018 ± 0.004 s(-1) (mean ± standard deviation, n = 6) for glioma, 0.009 ± 0.003 s(-1) for normal brain, and 0.005 ± 0.001 s(-1) for vasculature, whereas the lactate-to-pyruvate ratio, the metabolic marker used to date to identify tumor regions, was 0.36 ± 0.07 (mean ± SD), 0.24 ± 0.07, and 0.12 ± 0.02 for glioma, normal brain, and vasculature, respectively. The data suggest that the apparent conversion rate better differentiate glioma from normal brain (P = 0.001, n = 6) than the lactate-to-pyruvate ratio (P = 0.02).

  View details for DOI 10.1002/mrm.24181

  View details for Web of Science ID 000311398600022

  View details for PubMedID 22334279

  View details for PubMedCentralID PMC3376665

• Application of hyperpolarized [1-13C]lactate for the in vivo investigation of cardiac metabolism NMR IN BIOMEDICINE Mayer, D., Yen, Y., Josan, S., Park, J. M., Pfefferbaum, A., Hurd, R. E., Spielman, D. M. 2012; 25 (10): 1119-1124

  Abstract

  In addition to cancer imaging, (13) C-MRS of hyperpolarized pyruvate has also demonstrated utility for the investigation of cardiac metabolism and ischemic heart disease. Although no adverse effects have yet been reported for doses commonly used in vivo, high substrate concentrations have lead to supraphysiological pyruvate levels that can affect the underlying metabolism and should be considered when interpreting results. With lactate serving as an important energy source for the heart and physiological lactate levels one to two orders of magnitude higher than for pyruvate, hyperpolarized lactate could potentially be used as an alternative to pyruvate for probing cardiac metabolism. In this study, hyperpolarized [1-(13) C]lactate was used to acquire time-resolved spectra from the healthy rat heart in vivo and to measure dichloroacetate (DCA)-modulated changes in flux through pyruvate dehydrogenase (PDH). Both primary oxidation of lactate to pyruvate and subsequent conversion of pyruvate to alanine and bicarbonate could reliably be detected. Since DCA stimulates the activity of PDH through inhibition of PDH kinase, a more than 2.5-fold increase in bicarbonate-to-substrate ratio was found after administration of DCA, similar to the effect when using [1-(13) C]pyruvate as the substrate.

  View details for DOI 10.1002/nbm.2778

  View details for Web of Science ID 000308710400003

  View details for PubMedID 22278751

  View details for PubMedCentralID PMC3357452

• Neurometabolite Effects of Response to Quetiapine and Placebo in Adolescents with Bipolar Depression JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Chang, K., DelBello, M., Chu, W., Garrett, A., Kelley, R., Mills, N., Howe, M., Bryan, H., Adler, C., Eliassen, J., Spielman, D., Strakowski, S. M. 2012; 22 (4): 261-268

  Abstract

  Mood stabilizers have been reported to affect brain concentrations of myo-inositol (mI) and N-acetylaspartate (NAA). We examined the effects of quetiapine (QUET), an atypical antipsychotic, on these neurochemicals, and potential predictors of response to QUET in adolescents with bipolar depression.Twenty-six adolescents with bipolar depression participated in an 8-week placebo-controlled trial of QUET monotherapy. Subjects were scanned at baseline and after 8 weeks with proton magnetic resonance spectroscopy (1H-MRS) at 3T and 4T at two sites, with 8 cm(3) voxels placed in the right and left dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). LCModel was used to calculate absolute concentrations of NAA and mI.Twenty-six subjects had pre- and posttreatment scans (mean age=15.6 years, 9 boys). Of these subjects, 5 out of 16 subjects receiving QUET and 5 out of 10 receiving placebo (PBO) were responders (50% decrease in Children's Depression Rating Scale [CDRS] score). Although baseline ACC mI did not predict responder status, responders had significantly lower posttreatment ACC mI values than did nonresponders (3.27±.71 vs. 4.23±.70; p=0.004). There were no significant differences in the changes in ACC and DLPFC NAA levels in the QUET group compared with the PBO group (ACC: -0.55±1.3 vs.+0.25±1.5, p=0.23; right-DLPFC: -0.55±1.3 vs. 0.33±0.89, p=0.13; left-DLPFC: -0.04±0.91 vs.+0.29±0.61, p=0.41).We found that posttreatment, not baseline, ACC mI levels were associated with response to QUET in adolescents with bipolar depression. There were no differences in NAA concentration changes between the QUET and PBO groups. Larger studies including different brain regions would help to clarify the effects of QUET on neurochemistry in patients with bipolar disorder.

  View details for DOI 10.1089/cap.2011.0153

  View details for PubMedID 22849427

• Fast volumetric imaging of ethanol metabolism in rat liver with hyperpolarized [1-13C]pyruvate NMR IN BIOMEDICINE Josan, S., Spielman, D., Yen, Y., Hurd, R., Pfefferbaum, A., Mayer, D. 2012; 25 (8): 993-999

  Abstract

  Rapid volumetric imaging of hyperpolarized (13) C compounds allows the real-time measurement of metabolic activity and can be useful in distinguishing between normal and diseased tissues. This work extends a fast two-dimensional undersampled spiral MRSI sequence to provide volumetric coverage, acquiring a 16 × 16 × 12 matrix with a nominal isotropic resolution of 5 mm in 4.5 s. The rapid acquisition enables a high temporal resolution for dynamic imaging. This dynamic three-dimensional MRSI method was used to investigate hyperpolarized [1-(13) C]pyruvate metabolism modulated by the administration of ethanol in rat liver. A significant increase in the pyruvate to lactate conversion was observed in the liver as a result of the greater availability of NADH (nicotinamide adenine dinucleotide, reduced form) from ethanol metabolism.

  View details for DOI 10.1002/nbm.2762

  View details for Web of Science ID 000306178400005

  View details for PubMedID 22331837

  View details for PubMedCentralID PMC3366020

• Self-Refocused Adiabatic Pulse for Spin Echo Imaging at 7 T MAGNETIC RESONANCE IN MEDICINE Balchandani, P., Khalighi, M. M., Glover, G., Pauly, J., Spielman, D. 2012; 67 (4): 1077-1085

  Abstract

  Spin echo pulse sequences are used to produce clinically important T(2) contrast. However, conventional 180° radiofrequency pulses required to generate a spin echo are highly susceptible to the B(1) inhomogeneity at high magnetic fields such as 7 Tesla (7 T), resulting in varying signal and contrast over the region of interest. Adiabatic 180° pulses may be used to replace conventional 180° pulses in spin echo sequences to provide greater immunity to the inhomogeneous B(1) field at 7 T. However, because the spectral profile of an adiabatic 180° pulse has nonlinear phase, pairs of these pulses are needed for proper refocusing, resulting in increased radiofrequency power deposition and long minimum echo times. We used the adiabatic Shinnar Le-Roux method to generate a matched-phase adiabatic 90°-180° pulse pair to obviate the need for a second adiabatic 180° pulse for phase refocusing. The pulse pair was then reformulated into a single self-refocused pulse to minimize the echo time, and phantom and in vivo experiments were performed to validate pulse performance. The self-refocused adiabatic pulse produced transmit profiles that were substantially more uniform than those achieved using a conventional spin echo sequence.

  View details for DOI 10.1002/mrm.23089

  View details for Web of Science ID 000301533500021

  View details for PubMedID 21954048

  View details for PubMedCentralID PMC3548423

• Quantification of in vivo metabolic kinetics of hyperpolarized pyruvate in rat kidneys using dynamic C-13 MRSI NMR IN BIOMEDICINE Xu, T., Mayer, D., Gu, M., Yen, Y., Josan, S., Tropp, J., Pfefferbaum, A., Hurd, R., Spielman, D. 2011; 24 (8): 997-1005

  Abstract

  With signal-to-noise ratio enhancements on the order of 10,000-fold, hyperpolarized MRSI of metabolically active substrates allows the study of both the injected substrate and downstream metabolic products in vivo. Although hyperpolarized [1-(13)C]pyruvate, in particular, has been used to demonstrate metabolic activities in various animal models, robust quantification and metabolic modeling remain important areas of investigation. Enzyme saturation effects are routinely seen with commonly used doses of hyperpolarized [1-(13)C]pyruvate; however, most metrics proposed to date, including metabolite ratios, time-to-peak of metabolic products and single exchange rate constants, fail to capture these saturation effects. In addition, the widely used small-flip-angle excitation approach does not correctly model the inflow of fresh downstream metabolites generated proximal to the target slice, which is often a significant factor in vivo. In this work, we developed an efficient quantification framework employing a spiral-based dynamic spectroscopic imaging approach. The approach overcomes the aforementioned limitations and demonstrates that the in vivo (13)C labeling of lactate and alanine after a bolus injection of [1-(13)C]pyruvate is well approximated by saturatable kinetics, which can be mathematically modeled using a Michaelis-Menten-like formulation, with the resulting estimated apparent maximal reaction velocity V(max) and apparent Michaelis constant K(M) being unbiased with respect to critical experimental parameters, including the substrate dose, bolus shape and duration. Although the proposed saturatable model has a similar mathematical formulation to the original Michaelis-Menten kinetics, it is conceptually different. In this study, we focus on the (13)C labeling of lactate and alanine and do not differentiate the labeling mechanism (net flux or isotopic exchange) or the respective contribution of various factors (organ perfusion rate, substrate transport kinetics, enzyme activities and the size of the unlabeled lactate and alanine pools) to the labeling process.

  View details for DOI 10.1002/nbm.1719

  View details for Web of Science ID 000295293900009

  View details for PubMedID 21538639

  View details for PubMedCentralID PMC3169748

• In vivo MRSI of hyperpolarized [1-C-13]pyruvate metabolism in rat hepatocellular carcinoma NMR IN BIOMEDICINE Darpolor, M. M., Yen, Y., Chua, M., Xing, L., Clarke-Katzenberg, R. H., Shi, W., Mayer, D., Josan, S., Hurd, R. E., Pfefferbaum, A., Senadheera, L., So, S., Hofmann, L. V., Glazer, G. M., Spielman, D. M. 2011; 24 (5): 506-513

  Abstract

  Hepatocellular carcinoma (HCC), the primary form of human adult liver malignancy, is a highly aggressive tumor with average survival rates that are currently less than 1 year following diagnosis. Most patients with HCC are diagnosed at an advanced stage, and no efficient marker exists for the prediction of prognosis and/or response(s) to therapy. We have reported previously a high level of [1-(13)C]alanine in an orthotopic HCC using single-voxel hyperpolarized [1-(13)C]pyruvate MRS. In the present study, we implemented a three-dimensional MRSI sequence to investigate this potential hallmark of cellular metabolism in rat livers bearing HCC (n = 7 buffalo rats). In addition, quantitative real-time polymerase chain reaction was used to determine the mRNA levels of lactate dehydrogenase A, nicotinamide adenine (phosphate) dinucleotide dehydrogenase quinone 1 and alanine transaminase. The enzyme levels were significantly higher in tumor than in normal liver tissues within each rat, and were associated with the in vivo MRSI signal of [1-(13)C]alanine and [1-(13)C]lactate after a bolus intravenous injection of [1-(13)C]pyruvate. Histopathological analysis of these tumors confirmed the successful growth of HCC as a nodule in buffalo rat livers, revealing malignancy and hypervascular architecture. More importantly, the results demonstrated that the metabolic fate of [1-(13)C]pyruvate conversion to [1-(13)C]alanine significantly superseded that of [1-(13)C]pyruvate conversion to [1-(13)C]lactate, potentially serving as a marker of HCC tumors.

  View details for DOI 10.1002/nbm.1616

  View details for Web of Science ID 000291597200009

  View details for PubMedID 21674652

  View details for PubMedCentralID PMC3073155

• Detection of Inflammatory Arthritis by Using Hyperpolarized C-13-Pyruvate with MR Imaging and Spectroscopy RADIOLOGY MacKenzie, J. D., Yen, Y., Mayer, D., Tropp, J. S., Hurd, R. E., Spielman, D. M. 2011; 259 (2): 414-420

  Abstract

  To examine the feasibility of using magnetic resonance (MR) spectroscopy with hyperpolarized carbon 13 ((13)C)-labeled pyruvate to detect inflammation.The animal care and use committee approved all work with animals. Arthritis was induced in the right hind paw of six rats; the left hind paw served as an internal control. The lactate dehydrogenase-catalyzed conversion of pyruvate to lactate was measured in inflamed and control paws by using (13)C MR spectroscopy. Clinical and histologic data were obtained to confirm the presence and severity of arthritis. Hyperpolarized (13)C-pyruvate was intravenously injected into the rats before simultaneous imaging of both paws with (13)C MR spectroscopy. The Wilcoxon signed rank test was used to test for differences in metabolites between the control and arthritic paws.All animals showed findings of inflammation in the affected paws and no signs of arthritis in the control paws at both visible inspection (clinical index of 3 for arthritic paws and 0 for control paws) and histologic examination (histologic score of 3-5 for arthritic paws and 0 for control paws). Analysis of the spectroscopic profiles of (13)C-pyruvate and converted (13)C-lactate showed an increase in the amount of (13)C-lactate in inflamed paws (median lactate-to-pyruvate ratio, 0.50; mean lactate-to-pyruvate ratio ± standard deviation, 0.52 ± 0.16) versus control paws (median lactate-to-pyruvate ratio, 0.27; mean lactate-to-pyruvate ratio, 0.32 ± 0.11) (P < .03). The ratio of (13)C-lactate to total (13)C was also significantly increased in inflamed paws compared with control paws (P < .03).These results suggest that alterations in the conversion of pyruvate to lactate as detected with (13)C-MR spectroscopy may be indicative of the presence of inflammatory arthritis.

  View details for DOI 10.1148/radiol.10101921

  View details for Web of Science ID 000289667300013

  View details for PubMedID 21406626

  View details for PubMedCentralID PMC3079121

• Dynamic and High-Resolution Metabolic Imaging of Hyperpolarized [1-C-13]-Pyruvate in the Rat Brain Using a High-Performance Gradient Insert MAGNETIC RESONANCE IN MEDICINE Mayer, D., Yen, Y., Takahashi, A., Josan, S., Tropp, J., Rutt, B. K., Hurd, R. E., Spielman, D. M., Pfefferbaum, A. 2011; 65 (5): 1228-1233

  Abstract

  Fast chemical shift imaging (CSI) techniques are advantageous in metabolic imaging of hyperpolarized compounds due to the limited duration of the signal amplification. At the same time, reducing the acquisition time in hyperpolarized imaging does not necessarily lead to the conventional penalty in signal-to-noise ratio that occurs in imaging at thermal equilibrium polarization levels. Here a high-performance gradient insert was used in combination with undersampled spiral CSI to increase either the imaging speed or the spatial resolution of hyperpolarized (13)C metabolic imaging on a clinical 3T MR scanner. Both a single-shot sequence with a total acquisition time of 125 ms and a three-shot sequence with a nominal in-plane resolution of 1.5 mm were implemented. The k-space trajectories were measured and then used during image reconstruction. The technique was applied to metabolic imaging of the rat brain in vivo after the injection of hyperpolarized [1-(13)C]-pyruvate. Dynamic imaging afforded the measurement of region-of-interest-specific time courses of pyruvate and its metabolic products, while imaging at high spatial resolution was used to better characterize the spatial distribution of the metabolite signals.

  View details for DOI 10.1002/mrm.22707

  View details for Web of Science ID 000289760800003

  View details for PubMedID 21500253

  View details for PubMedCentralID PMC3126907

• Application of double spin echo spiral chemical shift imaging to rapid metabolic mapping of hyperpolarized [1-C-13]-pyruvate JOURNAL OF MAGNETIC RESONANCE Josan, S., Yen, Y., Hurd, R., Pfefferbaum, A., Spielman, D., Mayer, D. 2011; 209 (2): 332-336

  Abstract

  Undersampled spiral CSI (spCSI) using a free induction decay (FID) acquisition allows sub-second metabolic imaging of hyperpolarized ¹³C. Phase correction of the FID acquisition can be difficult, especially with contributions from aliased out-of-phase peaks. This work extends the spCSI sequence by incorporating double spin echo radiofrequency (RF) pulses to eliminate the need for phase correction and obtain high quality spectra in magnitude mode. The sequence also provides an added benefit of attenuating signal from flowing spins, which can otherwise contaminate signal in the organ of interest. The refocusing pulses can potentially lead to a loss of hyperpolarized magnetization in dynamic imaging due to flow of spins through the fringe field of the RF coil, where the refocusing pulses fail to provide complete refocusing. Care must be taken for dynamic imaging to ensure that the spins remain within the B₁-homogeneous sensitive volume of the RF coil.

  View details for DOI 10.1016/j.jmr.2011.01.010

  View details for Web of Science ID 000289270900030

  View details for PubMedID 21316280

  View details for PubMedCentralID PMC3072043

• Neurochemical deficits in the cerebellar vermis in child offspring of parents with bipolar disorder BIPOLAR DISORDERS Singh, M. K., Spielman, D., Libby, A., Adams, E., Acquaye, T., Howe, M., Kelley, R., Reiss, A., Chang, K. D. 2011; 13 (2): 189-197

  Abstract

  We aimed to compare concentrations of N-acetyl aspartate, myo-inositol, and other neurometabolites in the cerebellar vermis of offspring at risk for bipolar disorder (BD) and healthy controls to examine whether changes in these neuronal metabolite concentrations occur in at-risk offspring prior to the onset of mania.A total of 22 children and adolescents aged 9-17 years with a familial risk for bipolar I or II disorder [at-risk offspring with non-bipolar I disorder mood symptoms (AR)], and 25 healthy controls (HC) were examined using proton magnetic resonance spectroscopy at 3T to study metabolite concentrations in an 8-cc voxel in the cerebellar vermis.Decreased myo-inositol and choline concentrations in the vermis were seen in the AR group compared to HC (p<0.01).Decreased cellular metabolism and interference with second messenger pathways may be present in the cerebellar vermis in youth at risk for BD as evident by decreased myo-inositol and choline concentrations in this region. These results may be limited by a cross-sectional design, co-occurring diagnoses, and medication exposure. Longitudinal studies are necessary to determine whether early neurochemical changes can predict the development of mania. Improved methods for identifying children with certain neurochemical vulnerabilities may inform preventive and early intervention strategies prior to the onset of mania.

  View details for DOI 10.1111/j.1399-5618.2011.00902.x

  View details for PubMedID 21443573

• MR Spectroscopy for Assessment of Memantine Treatment in Mild to Moderate Alzheimer Dementia JOURNAL OF ALZHEIMERS DISEASE Ashford, J. W., Adamson, M., Beale, T., La, D., Hernandez, B., Noda, A., Rosen, A., O'Hara, R., Fairchild, J. K., Spielman, D., Yesavage, J. A. 2011; 26: 331-336

  Abstract

  Magnetic Resonance Spectroscopy (MRS) may provide a precise and reliable assessment of the extent and severity of neural tissue loss caused by various diseases. In particular, the N-Acetyl Aspartate (NAA) and Creatine (Cr) ratio has been found to be an indicator of the degree of neuronal loss in Alzheimer's disease (AD). Memantine is thought to benefit the AD brain by stabilizing the NMDA receptors on neurons in turn reducing excitotoxicity. Despite its effectiveness in treating moderate to severe AD, memantine has not had similar success in the treatment of mildly demented AD patients. The objective of this study was to test whether memantine would slow or prevent the loss of neurons in mild to moderate AD patients.A double-blind placebo-controlled study was designed to measure the effect of a year-long course of memantine in patients with a probable AD diagnosis with mild to moderate dementia. The primary outcome measure was stipulated to be change in MRS NAA/Cr ratio in inferior parietal cortex in memantine relative to the placebo treatment condition. The secondary outcome measures were changes in cognitive and function scale scores.This pilot study failed to demonstrate a benefit of memantine on the primary outcome measure, the inferior parietal NAA/Cr ratio, or the secondary outcome measures.More studies are needed to determine the effect of memantine on regions of the brain significantly affected by AD pathology.

  View details for DOI 10.3233/JAD-2011-0021

  View details for Web of Science ID 000297842800025

  View details for PubMedID 21971472

• MR Spectroscopy for Assessment of Memantine Treatment in Mild to Moderate Alzheimer Dementia HANDBOOK OF IMAGING THE ALZHEIMER BRAIN Ashford, J. W., Adamson, M., Beale, T., La, D., Hernandez, B., Noda, A., Rosen, A., O'Hara, R., Fairchild, J. K., Spielman, D., Yesavage, J. A., Ashford, J. W., Rosen, A., Adamson, M., Bayley, P., Sabri, O., Furst, A., Black, S. E., Weiner, M. 2011; 2: 599-604

  View details for DOI 10.3233/978-1-60750-793-2-599

  View details for Web of Science ID 000351445400053

• Magnetic Resonance Spectroscopy Introduction HANDBOOK OF IMAGING THE ALZHEIMER BRAIN Spielman, D., Ashford, J. W., Rosen, A., Adamson, M., Bayley, P., Sabri, O., Furst, A., Black, S. E., Weiner, M. 2011; 2: 559-560

  View details for DOI 10.3233/978-1-60750-793-2-559

  View details for Web of Science ID 000351445400048

• Imaging the Alzheimer Brain JOURNAL OF ALZHEIMERS DISEASE Ashford, J. W., Salehi, A., Furst, A., Bayley, P., Frisoni, G. B., Jack, C. R., Sabri, O., Adamson, M. M., Coburn, K. L., Olichney, J., Schuff, N., Spielman, D., Edland, S. D., Black, S., Rosen, A., Kennedy, D., Weiner, M., Perry, G. 2011; 26: 1-27

  View details for DOI 10.3233/JAD-2011-0073

  View details for Web of Science ID 000297842800001

  View details for PubMedID 21971448

• Cerebral dynamics and metabolism of hyperpolarized [1-C-13]pyruvate using time-resolved MR spectroscopic imaging JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Hurd, R. E., Yen, Y., Tropp, J., Pfefferbaum, A., Spielman, D. M., Mayer, D. 2010; 30 (10): 1734-1741

  Abstract

  Dynamic hyperpolarized [1-(13)C]pyruvate metabolic imaging in the normal anesthetized rat brain is demonstrated on a clinical 3-T magnetic resonance imaging scanner. A 12-second bolus injection of hyperpolarized [1-(13)C]pyruvate is imaged at a 3-second temporal resolution. The observed dynamics are evaluated with regard to cerebral blood volume (CBV), flow, transport, and metabolic exchange with the cerebral lactate pool. A model for brain [1-(13)C]lactate, based on blood-brain transport kinetics, CBV, and the observed pyruvate dynamics is described.

  View details for DOI 10.1038/jcbfm.2010.93

  View details for Web of Science ID 000282382200007

  View details for PubMedID 20588318

  View details for PubMedCentralID PMC2975615

• Designing Adiabatic Radio Frequency Pulses Using the Shinnar-Le Roux Algorithm MAGNETIC RESONANCE IN MEDICINE Balchandani, P., Pauly, J., Spielman, D. 2010; 64 (3): 843-851

  Abstract

  Adiabatic pulses are a special class of radio frequency (RF) pulses that may be used to achieve uniform flip angles in the presence of a nonuniform B(1) field. In this work, we present a new, systematic method for designing high-bandwidth (BW), low-peak-amplitude adiabatic RF pulses that utilizes the Shinnar-Le Roux (SLR) algorithm for pulse design. Currently, the SLR algorithm is extensively employed to design nonadiabatic pulses for use in magnetic resonance imaging and spectroscopy. We have adapted the SLR algorithm to create RF pulses that also satisfy the adiabatic condition. By overlaying sufficient quadratic phase across the spectral profile before the inverse SLR transform, we generate RF pulses that exhibit the required spectral characteristics and adiabatic behavior. Application of quadratic phase also distributes the RF energy more uniformly, making it possible to obtain the same spectral BW with lower RF peak amplitude. The method enables the pulse designer to specify spectral profile parameters and the degree of quadratic phase before pulse generation. Simulations and phantom experiments demonstrate that RF pulses designed using this new method behave adiabatically.

  View details for DOI 10.1002/mrm.22473

  View details for Web of Science ID 000281346300025

  View details for PubMedID 20806378

  View details for PubMedCentralID PMC2975518

• In vivo application of sub-second spiral chemical shift imaging (CSI) to hyperpolarized C-13 metabolic imaging: Comparison with phase-encoded CSI JOURNAL OF MAGNETIC RESONANCE Mayer, D., Yen, Y., Levin, Y. S., Tropp, J., Pfefferbaum, A., Hurd, R. E., Spielman, D. M. 2010; 204 (2): 340-345

  Abstract

  A fast spiral chemical shift imaging (CSI) has been developed to address the challenge of the limited acquisition window in hyperpolarized (13)C metabolic imaging. The sequence exploits the sparsity of the spectra and prior knowledge of resonance frequencies to reduce the measurement time by undersampling the data in the spectral domain. As a consequence, multiple reconstructions are necessary for any given data set as only frequency components within a selected bandwidth are reconstructed "in-focus" while components outside that band are severely blurred ("spectral tomosynthesis"). A variable-flip-angle scheme was used for optimal use of the longitudinal magnetization. The sequence was applied to sub-second metabolic imaging of the rat in vivo after injection of hyperpolarized [1-(13)C]-pyruvate on a clinical 3T MR scanner. The comparison with conventional CSI based on phase encoding showed similar signal-to-noise ratio (SNR) and spatial resolution in metabolic maps for the substrate and its metabolic products lactate, alanine, and bicarbonate, despite a 50-fold reduction in scan time for the spiral CSI acquisition. The presented results demonstrate that dramatic reductions in scan time are feasible in hyperpolarized (13)C metabolic imaging without a penalty in SNR or spatial resolution.

  View details for DOI 10.1016/j.jmr.2010.03.005

  View details for Web of Science ID 000278162300021

  View details for PubMedID 20346717

  View details for PubMedCentralID PMC2893149

• Brain glutamatergic characteristics of pediatric offspring of parents with bipolar disorder PSYCHIATRY RESEARCH-NEUROIMAGING Singh, M., Spielman, D., Adleman, N., Alegria, D., Howe, M., Reiss, A., Chang, K. 2010; 182 (2): 165-171

  Abstract

  We wished to determine whether decreases in prefrontal glutamate concentrations occur in offspring of parents with bipolar disorder with and at high risk for mania. Sixty children and adolescents, 9-18 years old, of parents with bipolar I or II disorder (20 offspring with established history of mania, "BD", 20 offspring with symptoms subsyndromal to mania, "SS", and 20 healthy controls "HC") were examined using proton magnetic resonance spectroscopy at 3T to study glutamatergic metabolite concentrations in the anterior cingulate cortex (ACC). A signal for reductions in absolute glutamate concentrations in the ACC was seen in the BD compared with HC and SS groups. No other statistically significant differences among groups were found. Offspring of parents with BD with prior histories of mania may have disruptions in glutamatergic function compared with HC or children at risk for BD who have not yet developed mania. Longitudinal studies are necessary to confirm whether prefrontal glutamate decreases only after the onset of full mania.

  View details for DOI 10.1016/j.pscychresns.2010.01.003

  View details for PubMedID 20413280

• Metabolic Imaging in the Anesthetized Rat Brain Using Hyperpolarized [1-C-13] Pyruvate and [1-C-13] Ethyl Pyruvate MAGNETIC RESONANCE IN MEDICINE Hurd, R. E., Yen, Y., Mayer, D., Chen, A., Wilson, D., Kohler, S., Bok, R., Vigneron, D., Kurhanewicz, J., Tropp, J., Spielman, D., Pfefferbaum, A. 2010; 63 (5): 1137-1143

  Abstract

  Formulation, polarization, and dissolution conditions were developed to obtain a stable hyperpolarized solution of [1-(13)C]-ethyl pyruvate. A maximum tolerated concentration and injection rate were determined, and (13)C spectroscopic imaging was used to compare the uptake of hyperpolarized [1-(13)C]-ethyl pyruvate relative to hyperpolarized [1-(13)C]-pyruvate into anesthetized rat brain. Hyperpolarized [1-(13)C]-ethyl pyruvate and [1-(13)C]-pyruvate metabolic imaging in normal brain is demonstrated and quantified in this feasibility and range-finding study.

  View details for DOI 10.1002/mrm.22364

  View details for Web of Science ID 000277098100001

  View details for PubMedID 20432284

  View details for PubMedCentralID PMC2890241

• Evaluation of Dynamic Contrast-Enhanced MRI in Detecting Renal Scarring in a Rat Injury Model JOURNAL OF MAGNETIC RESONANCE IMAGING Wang, B., Sommer, G., Spielman, D., Shortliffe, L. M. 2010; 31 (5): 1132-1136

  Abstract

  To create a reliable rat model with small renal cortical scars and evaluate the accuracy and sensitivity of dynamic contrast-enhanced MRI in detecting the kinds of lesions that are associated with reflux nephropathy.In 16 rats, three unilateral renal cortical lesions were created using either electrocautery or pure alcohol with the contralateral kidney serving as control. MRI on a 1.5 Tesla GE Signa was performed 10-14 days after surgery. After bolus injection of 0.2 mM/Kg Gd-DTPA, sequential MRI acquisitions were performed using a 4-inch quadrature birdcage coil. Renal and scar volumes and pathology were compared after scanning and killing.Of the 48 points of injury, 40 (83%) in the 16 rats were detected grossly. Under microscopy, 36 injuries (75%) were detected on mid-kidney cross-sections. The average lesion was 4.2 mm(3) corresponding to 0.5% of the kidney volume. Using pathological findings as the gold standard, the sensitivity and specificity of scar detection using MRI was 69% and 93%, respectively.A rat model was created to demonstrate the sensitivity of dynamic contrast-enhanced MRI for detecting renal scars. Alcohol and electrocautery created reliable renal scars that were confirmed pathologically. MRI detected these lesions that averaged 4.2 mm(3) (0.5% total renal volume) with sensitivity and specificity of 69% and 93%, respectively.

  View details for DOI 10.1002/jmri.22027

  View details for Web of Science ID 000277397100012

  View details for PubMedID 20432348

  View details for PubMedCentralID PMC2921162

• T-2 relaxation times of C-13 metabolites in a rat hepatocellular carcinoma model measured in vivo using C-13-MRS of hyperpolarized [1-C-13]pyruvate NMR IN BIOMEDICINE Yen, Y., Le Roux, P., Mayer, D., King, R., Spielman, D., Tropp, J., Pauly, K. B., Pfefferbaum, A., Vasanawala, S., Hurd, R. 2010; 23 (4): 414-423

  Abstract

  A single-voxel Carr-Purcell-Meibloom-Gill sequence was developed to measure localized T(2) relaxation times of (13)C-labeled metabolites in vivo for the first time. Following hyperpolarized [1-(13)C]pyruvate injections, pyruvate and its metabolic products, alanine and lactate, were observed in the liver of five rats with hepatocellular carcinoma and five healthy control rats. The T(2) relaxation times of alanine and lactate were both significantly longer in HCC tumors than in normal livers (p < 0.002). The HCC tumors also showed significantly higher alanine signal relative to the total (13)C signal than normal livers (p < 0.006). The intra- and inter-subject variations of the alanine T(2) relaxation time were 11% and 13%, respectively. The intra- and inter-subject variations of the lactate T(2) relaxation time were 6% and 7%, respectively. The intra-subject variability of alanine to total carbon ratio was 16% and the inter-subject variability 28%. The intra-subject variability of lactate to total carbon ratio was 14% and the inter-subject variability 20%. The study results show that the signal level and relaxivity of [1-(13)C]alanine may be promising biomarkers for HCC tumors. Its diagnostic values in HCC staging and treatment monitoring are yet to be explored.

  View details for DOI 10.1002/nbm.1481

  View details for Web of Science ID 000277525800011

  View details for PubMedID 20175135

  View details for PubMedCentralID PMC2891253

• Breathheld Autocalibrated Phase-Contrast Imaging JOURNAL OF MAGNETIC RESONANCE IMAGING Lew, C., Alley, M. T., Spielman, D. M., Bammer, R., Chan, F. P. 2010; 31 (4): 1004-1014

  Abstract

  To compare generalized autocalibrating partially parallel acquisitions (GRAPPA), modified sensitivity encoding (mSENSE), and SENSE in phase-contrast magnetic resonance imaging (PC-MRI) applications.Aliasing of the torso can occur in PC-MRI applications. If the data are further undersampled for parallel imaging, SENSE can be problematic in correctly unaliasing signals due to coil sensitivity maps that do not match that of the aliased volume. Here, a method for estimating coil sensitivities in flow applications is described. Normal volunteers (n = 5) were scanned on a 1.5 T MRI scanner and underwent PC-MRI scans using GRAPPA, mSENSE, SENSE, and conventional PC-MRI acquisitions. Peak velocity and flow through the aorta and pulmonary artery were evaluated.Bland-Altman statistics for flow in the aorta and pulmonary artery acquired with mSENSE and GRAPPA methods (R = 2 and R = 3 cases) have comparable mean differences to flow acquired with conventional PC-MRI. GRAPPA and mSENSE PC-MRI have more robust measurements than SENSE when there is aliasing artifact caused by insufficient coil sensitivity maps. For peak velocity, there are no considerable differences among the mSENSE, GRAPPA, and SENSE reconstructions and are comparable to conventional PC-MRI.Flow measurements of images reconstructed with autocalibration techniques have comparable agreement with conventional PC-MRI and provide robust measurements in the presence of wraparound.

  View details for DOI 10.1002/jmri.22127

  View details for Web of Science ID 000276328200028

  View details for PubMedID 20373447

  View details for PubMedCentralID PMC2903748

• Hyperpolarized C-13 MRSI for Therapeutic Response Monitoring of Prostate Cancer to Radiotherapy 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Senadheera, L., Mayer, D., Darpolor, M. M., Yen, Y., Luong, R., Spielman, D. M., Xing, L. ELSEVIER SCIENCE INC. 2010: S116–S116

  View details for Web of Science ID 000288775700247

• Methods for Metabolic Evaluation of Prostate Cancer Cells Using Proton and C-13 HR-MAS Spectroscopy and [3-C-13] Pyruvate as a Metabolic Substrate MAGNETIC RESONANCE IN MEDICINE Levin, Y. S., Albers, M. J., Butler, T. N., Spielman, D., Peehl, D. M., Kurhanewicz, J. 2009; 62 (5): 1091-1098

  Abstract

  Prostate cancer has been shown to undergo unique metabolic changes associated with neoplastic transformation, with associated changes in citrate, alanine, and lactate concentrations. (13)C high resolution-magic angle spinning (HR-MAS) spectroscopy provides an opportunity to simultaneously investigate the metabolic pathways implicated in these changes by using (13)C-labeled substrates as metabolic probes. In this work, a method to reproducibly interrogate metabolism in prostate cancer cells in primary culture was developed using HR-MAS spectroscopy. Optimization of cell culture protocols, labeling parameters, harvesting, storage, and transfer was performed. Using [3-(13)C] pyruvate as a metabolic probe, (1)H and (13)C HR-MAS spectroscopy was used to quantify the net amount and fractional enrichment of several labeled metabolites that evolved in multiple cell samples from each of five different prostate cancers. Average enrichment across all cancers was 32.4 +/- 5.4% for [3-(13)C] alanine, 24.5 +/- 5.4% for [4-(13)C] glutamate, 9.1 +/- 2.5% for [3-(13)C] glutamate, 25.2 +/- 5.7% for [3-(13)C] aspartate, and 4.2 +/- 1.0% for [3-(13)C] lactate. Cell samples from the same parent population demonstrated reproducible fractional enrichments of alanine, glutamate, and aspartate to within 12%, 10%, and 10%, respectively. Furthermore, the cells produced a significant amount of [4-(13)C] glutamate, which supports the bioenergetic theory for prostate cancer. These methods will allow further characterization of metabolic properties of prostate cancer cells in the future. Magn Reson Med, 2009. (c) 2009 Wiley-Liss, Inc.

  View details for DOI 10.1002/mrm.22120

  View details for Web of Science ID 000271431200001

  View details for PubMedID 19780158

  View details for PubMedCentralID PMC2783184

• Application of Subsecond Spiral Chemical Shift Imaging to Real-Time Multislice Metabolic Imaging of the Rat In Vivo after Injection of Hyperpolarized C-13(1)-Pyruvate MAGNETIC RESONANCE IN MEDICINE Mayer, D., Yen, Y., Tropp, J., Pfefferbaum, A., Hurd, R. E., Spielman, D. M. 2009; 62 (3): 557-564

  Abstract

  Dynamic nuclear polarization can create hyperpolarized compounds with MR signal-to-noise ratio enhancements on the order of 10,000-fold. Both exogenous and normally occurring endogenous compounds can be polarized, and their initial concentration and downstream metabolic products can be assessed using MR spectroscopy. Given the transient nature of the hyperpolarized signal enhancement, fast imaging techniques are a critical requirement for real-time metabolic imaging. We report on the development of an ultrafast, multislice, spiral chemical shift imaging sequence, with subsecond acquisition time, achieved on a clinical MR scanner. The technique was used for dynamic metabolic imaging in rats, with measurement of time-resolved spatial distributions of hyperpolarized (13)C(1)-pyruvate and metabolic products (13)C(1)-lactate and (13)C(1)-alanine, with a temporal resolution of as fast as 1 s. Metabolic imaging revealed different signal time courses in liver from kidney. These results demonstrate the feasibility of real-time, hyperpolarized metabolic imaging and highlight its potential in assessing organ-specific kinetic parameters.

  View details for DOI 10.1002/mrm.22041

  View details for Web of Science ID 000269404900001

  View details for PubMedID 19585607

  View details for PubMedCentralID PMC2782691

• Visualizing Implanted Tumors in Mice with Magnetic Resonance Imaging Using Magnetotactic Bacteria CLINICAL CANCER RESEARCH Benoit, M. R., Mayer, D., Barak, Y., Chen, I. Y., Hu, W., Cheng, Z., Wang, S. X., Spielman, D. M., Gambhir, S. S., Matin, A. 2009; 15 (16): 5170-5177

  Abstract

  To determine if magnetotactic bacteria can target tumors in mice and provide positive contrast for visualization using magnetic resonance imaging.The ability of the magnetotactic bacterium, Magnetospirillum magneticum AMB-1 (referred to from here as AMB-1), to confer positive magnetic resonance imaging contrast was determined in vitro and in vivo. For the latter studies, AMB-1 were injected either i.t. or i.v. Bacterial growth conditions were manipulated to produce small (approximately 25-nm diameter) magnetite particles, which were observed using transmission electron microscopy. Tumor targeting was confirmed using 64Cu-labeled bacteria and positron emission tomography and by determination of viable cell counts recovered from different organs and the tumor.We show that AMB-1 bacteria with small magnetite particles generate T1-weighted positive contrast, enhancing in vivo visualization by magnetic resonance imaging. Following i.v. injection of 64Cu-labeled AMB-1, positron emission tomography imaging revealed increasing colonization of tumors and decreasing infection of organs after 4 hours. Viable cell counts showed that, by day 6, the bacteria had colonized tumors but were cleared completely from other organs. Magnetic resonance imaging showed a 1.22-fold (P = 0.003) increased positive contrast in tumors on day 2 and a 1.39-fold increase (P = 0.0007) on day 6.Magnetotactic bacteria can produce positive magnetic resonance imaging contrast and colonize mouse tumor xenografts, providing a potential tool for improved magnetic resonance imaging visualization in preclinical and translational studies to track cancer.

  View details for DOI 10.1158/1078-0432.CCR-08-3206

  View details for Web of Science ID 000269024900019

  View details for PubMedID 19671860

  View details for PubMedCentralID PMC3409839

• In Vivo Measurement of Ethanol Metabolism in the Rat Liver Using Magnetic Resonance Spectroscopy of Hyperpolarized [1-C-13]Pyruvate MAGNETIC RESONANCE IN MEDICINE Spielman, D. M., Mayer, D., Yen, Y., Tropp, J., Hurd, R. E., Pfefferbaum, A. 2009; 62 (2): 307-313

  Abstract

  [1-(13)C]pyruvate is a readily polarizable substrate that has been the subject of numerous magnetic resonance spectroscopy (MRS) studies of in vivo metabolism. In this work (13)C-MRS of hyperpolarized [1-(13)C]pyruvate was used to interrogate a metabolic pathway involved in neither aerobic nor anaerobic metabolism. In particular, ethanol consumption leads to altered liver metabolism, which when excessive is associated with adverse medical conditions including fatty liver disease, hepatitis, cirrhosis, and cancer. Here we present a method for noninvasively monitoring this important process in vivo. Following the bolus injection of hyperpolarized [1-(13)C]pyruvate, we demonstrate a significantly increased rat liver lactate production rate with the coadministration of ethanol (P = 0.0016 unpaired t-test). The affect is attributable to increased liver nicotinamide adenine dinucleotide (NADH) associated with ethanol metabolism in combination with NADH's role as a coenzyme in pyruvate-to-lactate conversion. Beyond studies of liver metabolism, this novel in vivo assay of changes in NADH levels makes hyperpolarized [1-(13)C]pyruvate a potentially viable substrate for studying the multiple in vivo metabolic pathways that use NADH (or NAD(+)) as a coenzyme, thus broadening the range of applications that have been discussed in the literature to date.

  View details for DOI 10.1002/mrm.21998

  View details for Web of Science ID 000268432400005

  View details for PubMedID 19526498

  View details for PubMedCentralID PMC2780439

• Self-Refocused Spatial-Spectral Pulse for Positive Contrast Imaging of Cells Labeled with SPIO Nanoparticles MAGNETIC RESONANCE IN MEDICINE Balchandani, P., Yamada, M., Pauly, J., Yang, P., Spielman, D. 2009; 62 (1): 183-192

  Abstract

  MRI has been used extensively to noninvasively track the location of cells labeled with superparamagnetic iron-oxide nanoparticles (SPIOs) in vivo. Typically, SPIOs are employed as a negative contrast agent which makes it difficult to differentiate labeled cells from extraneous sources of inhomogeneity and actual voids in the image. As a result, several novel approaches have been put forth to obtain positive contrast from SPIOs. One technique proposed by Cunningham et al. utilizes spectrally selective pulses to excite and refocus spins in the vicinity of the SPIOs. Although the frequency selectivity of this technique provides effective positive contrast, the lack of slice selectivity results in interfering signal from sources of off-resonance outside the slice of interest. We have developed a self-refocused spatial-spectral (SR-SPSP) pulse to achieve slice-selective spin-echo imaging of off-resonant spins. Using a self-refocused pulse affords flexibility in echo-time selection since the spin echo may be placed at any time after the end of the pulse. The spatial selectivity achieved by the SR-SPSP RF pulse eliminates background signal from out-of-slice regions and reduces the on-resonant water suppression requirements. Phantom and in vivo data demonstrate that positive contrast and slice-selectivity are achieved using this novel RF pulse.

  View details for DOI 10.1002/mrm.21973

  View details for PubMedID 19449385

• Neurochemical substrates of risk in pediatric offspring of parents with bipolar disorder 8th International Conference on Bipolar Disorder Singh, M. K., Spielman, D., Kelley, R., ALEGRIA, D., Howe, M., Reiss, A., Chang, K. WILEY-BLACKWELL. 2009: 80–80

  View details for Web of Science ID 000268963500217

• Parallel Spectroscopic Imaging Reconstruction with Arbitrary Trajectories Using k-Space Sparse Matrices MAGNETIC RESONANCE IN MEDICINE Gu, M., Liu, C., Spielman, D. M. 2009; 61 (2): 267-272

  Abstract

  Parallel imaging reconstruction has been successfully applied to magnetic resonance spectroscopic imaging (MRSI) to reduce scan times. For undersampled k-space data on a Cartesian grid, the reconstruction can be achieved in image domain using a sensitivity encoding (SENSE) algorithm for each spectral data point. Alternative methods for reconstruction with undersampled Cartesian k-space data are the SMASH and GRAPPA algorithms that do the reconstruction in the k-space domain. To reconstruct undersampled MRSI data with arbitrary k-space trajectories, image-domain-based iterative SENSE algorithm has been applied at the cost of long computing times. In this paper, a new k-space domain-based parallel spectroscopic imaging reconstruction with arbitrary k-space trajectories using k-space sparse matrices is applied to MRSI with spiral k-space trajectories. The algorithm achieves MRSI reconstruction with reduced memory requirements and computing times. The results are demonstrated in both phantom and in vivo studies. Spectroscopic images very similar to that reconstructed with fully sampled spiral k-space data are obtained at different reduction factors.

  View details for DOI 10.1002/mrm.21838

  View details for Web of Science ID 000262871300004

  View details for PubMedID 19165883

  View details for PubMedCentralID PMC2754750

• B1 and T1 Insensitive Water and Lipid Suppression Using Optimized Multiple Frequency-Selective Preparation Pulses for Whole-Brain 1H Spectroscopic Imaging at 3T MAGNETIC RESONANCE IN MEDICINE Gu, M., Spielman, D. M. 2009; 61 (2): 462-466

  Abstract

  A new method for the simultaneous suppression of water and lipid resonances using a series of dual-band frequency-selective radiofrequency (RF) pulses with associated dephasing gradients is presented. By optimizing the nutation angles of the individual pulses, the water and lipid suppression is made insensitive to a range of both T1-relaxation times and B1 inhomogeneities. The method consists only of preparatory RF pulses and thus can be combined with a wide variety of MRSI schemes including both long and short TE studies. Simulations yield suppression factors, in the presence of +/-20% B1 inhomogeneity, on the order of 100 for lipid peaks with three different T1s (300 ms, 310 ms, and 360 ms), and water peaks with T1s ranging from 0.8 s to 4 s. Excellent in vivo study performance is demonstrated using a 3 Tesla volumetric proton spectroscopic imaging (1H-MRSI) sequence for measuring the primary brain metabolites peaks of choline (Cho), creatine (Cr), and N-acetyl aspartate (NAA).

  View details for DOI 10.1002/mrm.21843

  View details for Web of Science ID 000262871300025

  View details for PubMedID 19161165

• Gradient Moment Compensated Magnetic Resonance Spectroscopic Imaging MAGNETIC RESONANCE IN MEDICINE Kim, D., Gu, M., Spielman, D. M. 2009; 61 (2): 457-461

  Abstract

  Spectroscopic imaging applications outside of the brain can suffer from artifacts due to inherent long scan times and susceptibility to motion. A fast spectroscopic imaging sequence has been devised with reduced sensitivity to motion. The sequence uses oscillating readout gradients and acquires k-space data in a spiral out-in fashion, which allows fast k-space coverage. We show that a spiral out-in readout acquisition is characterized by small gradient moments, reducing sensitivity to motion-induced artifacts. Data are acquired comparing the sequence to normal phase encoded spectroscopic imaging and conventional spiral spectroscopic imaging protocols. In addition, in vivo data are acquired from the liver, demonstrating potential usage as a multivoxel fat/water spectroscopic imaging tool. Results indicate that in the presence of motion, ghosting effects are reduced while metabolite signal increases of approximately 10% can be achieved.

  View details for DOI 10.1002/mrm.21832

  View details for Web of Science ID 000262871300024

  View details for PubMedID 19161164

  View details for PubMedCentralID PMC2835400

• Fast 3D H-1 MRSI of the Corticospinal Tract in Pediatric Brain JOURNAL OF MAGNETIC RESONANCE IMAGING Kim, D., Gu, M., Cunningham, C., Chen, A., Baumer, F., Glenn, O. A., Vigneron, D. B., Spielman, D. M., Barkovich, A. J. 2009; 29 (1): 1-6

  Abstract

  To develop a (1)H magnetic resonance spectroscopic imaging (MRSI) sequence that can be used to image infants/children at 3T and by combining it with diffusion tensor imaging (DTI) tractography, extract relevant metabolic information corresponding to the corticospinal tract (CST).A fast 3D MRSI sequence was developed for pediatric neuroimaging at 3T using spiral k-space readout and dual band RF pulses (32 x 32 x 8 cm field of view [FOV], 1 cc iso-resolution, TR/TE = 1500/130, 6:24 minute scan). Using DTI tractography to identify the motor tracts, spectra were extracted from the CSTs and quantified. Initial data from infants/children with suspected motor delay (n = 5) and age-matched controls (n = 3) were collected and N-acetylaspartate (NAA) ratios were quantified.The average signal-to-noise ratio of the NAA peak from the studies was approximately 22. Metabolite profiles were successfully acquired from the CST by using DTI tractography. Decreased NAA ratios in those with motor delay compared to controls of approximately 10% at the CST were observed.A fast and robust 3D MRSI technique targeted for pediatric neuroimaging has been developed. By combining with DTI tractography, metabolic information from the CSTs can be retrieved and estimated. By combining DTI and 3D MRSI, spectral information from various tracts can be obtained and processed.

  View details for DOI 10.1002/jmri.21394

  View details for Web of Science ID 000262168200001

  View details for PubMedID 19097091

  View details for PubMedCentralID PMC2832220

• In vivo Detection of Radiation-induced Tissue Alterations by Hyperpolarized C-13 Metabolic Imaging 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Senadheera, L., Mayer, D., Darpolor, M. M., Yen, Y., Spielman, D. M., Xing, L. ELSEVIER SCIENCE INC. 2009: S48–S49

  View details for Web of Science ID 000270573600103

• MRI and H-1 MRS of The Breast: Presence of a Choline Peak as Malignancy Marker is Related to k21 Value of the Tumor in Patients with Invasive Ductal Carcinoma BREAST JOURNAL Geraghty, P. R., van den Bosch, M. A., Spielman, D. M., Hunjan, S., Birdwell, R. L., Fong, K. J., Stables, L. A., Zakhour, M., Herfkens, R. J., Ikeda, D. M. 2008; 14 (6): 574-580

  Abstract

  To assess which specific morphologic features, enhancement patterns, or pharmacokinetic parameters on breast Magnetic Resonance Imaging (MRI) could predict a false-negative outcome of Proton MR Spectroscopy ((1)H MRS) exam in patients with invasive breast cancer. Sixteen patients with invasive ductal carcinoma of the breast were prospectively included and underwent both, contrast-enhanced breast MRI and (1)H MRS examination of the breast. The MR images were reviewed and the lesions morphologic features, enhancement patterns and pharmacokinetic parameters (k21-value) were scored according to the ACR BI-RADS-MRI lexicon criteria. For the in vivo MRS studies, each spectrum was evaluated for the presence of choline based on consensus reading. Breast MRI and (1)H MRS data were compared to histopathologic findings. In vivo (1)H MRS detected a choline peak in 14/16 (88%) cancers. A false-negative (1)H MRS study occurred in 2/16 (14%) cancer patients. K21 values differed between both groups: the 14 choline positive cancers had k21 values ranging from 0.01 to 0.20/second (mean 0.083/second), whereas the two choline-negative cancers showed k21 values of 0.03 and 0.05/second, respectively (mean 0.040/second). Also enhancement kinetics did differ between both groups; typically both cancers that were choline-negative showed a late phase plateau (100%), whereas this was only shown in 5/14 (36%) of the choline positive cases. There was no difference between both groups with regard to morphologic features on MRI. This study showed that false-negative (1)H MRS examinations do occur in breast cancer patients, and that the presence of a choline peak on (1)H MRS as malignancy marker is related to the k21 value of the invasive tumor being imaged.

  View details for DOI 10.1111/j.1524-4741.2008.00650.x

  View details for Web of Science ID 000261085300011

  View details for PubMedID 19000051

  View details for PubMedCentralID PMC2842578

• Reproducibility study of whole-brain H-1 spectroscopic imaging with automated quantification MAGNETIC RESONANCE IN MEDICINE Gu, M., Kim, D., Mayer, D., Sullivan, E. V., Pfefferbaum, A., Spielman, D. M. 2008; 60 (3): 542-547

  Abstract

  A reproducibility study of proton MR spectroscopic imaging ((1)H-MRSI) of the human brain was conducted to evaluate the reliability of an automated 3D in vivo spectroscopic imaging acquisition and associated quantification algorithm. A PRESS-based pulse sequence was implemented using dualband spectral-spatial RF pulses designed to fully excite the singlet resonances of choline (Cho), creatine (Cre), and N-acetyl aspartate (NAA) while simultaneously suppressing water and lipids; 1% of the water signal was left to be used as a reference signal for robust data processing, and additional lipid suppression was obtained using adiabatic inversion recovery. Spiral k-space trajectories were used for fast spectral and spatial encoding yielding high-quality spectra from 1 cc voxels throughout the brain with a 13-min acquisition time. Data were acquired with an 8-channel phased-array coil and optimal signal-to-noise ratio (SNR) for the combined signals was achieved using a weighting based on the residual water signal. Automated quantification of the spectrum of each voxel was performed using LCModel. The complete study consisted of eight healthy adult subjects to assess intersubject variations and two subjects scanned six times each to assess intrasubject variations. The results demonstrate that reproducible whole-brain (1)H-MRSI data can be robustly obtained with the proposed methods.

  View details for DOI 10.1002/mrm.21713

  View details for Web of Science ID 000259053900006

  View details for PubMedID 18727040

• Can magnetic resonance spectroscopy predict neurodevelopmental outcome in very low birth weight preterm infants? Annual Meeting of the Pediatric-Academic-Societies/Society-of-Pediatric-Research Augustine, E. M., Spielman, D. M., Barnes, P. D., Sutcliffe, T. L., Dermon, J. D., Mirmiran, M., Clayton, D. B., Ariagno, R. L. NATURE PUBLISHING GROUP. 2008: 611–18

  Abstract

  To determine if metabolite ratios at near-term age predict outcome in very low birth weight preterm infants at 18 to 24 months adjusted age.Thirty-six infants (birth weight

  View details for DOI 10.1038/jp.2008.66

  View details for Web of Science ID 000258990600005

  View details for PubMedID 18615089

  View details for PubMedCentralID PMC2844764

• In vivo H-1 magnetic resonance spectroscopy of lactate in patients with Stage IV head and neck squamous cell carcinoma 49th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Le, Q., Koong, A., Lieskovsky, Y. Y., Narasimhan, B., Graves, E., Pinto, H., Brown, J. M., Spielman, D. ELSEVIER SCIENCE INC. 2008: 1151–57

  Abstract

  To investigate in vivo(1)H magnetic resonance spectroscopy imaging of lactate for assessing tumor hypoxia in head and neck cancers and to determine its utility in predicting the response and outcomes.Volume-localized lactate-edited (1)H magnetic resonance spectroscopy at 1.5 T was performed in vivo on involved neck nodes and control subcutaneous tissues in 36 patients with Stage IV head and neck cancer. The signal intensities (SIs) of lactate, choline, and creatine and the choline/creatine ratio were measured. The tumor partial pressure of oxygen (pO(2)) was obtained in the same lymph node before MRS. Patients were treated with either two cycles of induction chemotherapy (tirapazamine, cisplatin, 5-fluorouracil) followed by simultaneous chemoradiotherapy or the same regimen without tirapazamine. The lactate SI and the choline/creatine ratio correlated with the tumor pO(2), nodal response, and locoregional control.The lactate SI was greater for the involved nodes (median, 0.25) than for the subcutaneous tissue (median, 0.04; p = 0.07). No significant correlation was found between the lactate SI and tumor pO(2) (mean, 0.46 +/- 0.10 for hypoxic nodes [pO(2) < or =10 mm Hg, n = 15] vs. 0.36 +/- 0.07 for nonhypoxic nodes [pO(2) >10 mm Hg, n = 21], p = 0.44). A significant correlation was found between the choline/creatine ratios and tumor pO(2) (mean, 2.74 +/- 0.34 for hypoxic nodes vs. 1.78 +/- 0.31 for nonhypoxic nodes, p = 0.02). No correlation was found between the lactate SI and the complete nodal response (p = 0.52) or locoregional control rates.The lactate SI did not correlate with tumor pO(2), treatment response, or locoregional control. Additional research is needed to refine this technique.

  View details for DOI 10.1016/j.ijrobp.2007.11.030

  View details for Web of Science ID 000257299200025

  View details for PubMedID 18258377

  View details for PubMedCentralID PMC2601688

• Fat suppression for H-1 MRSI at 7T using spectrally selective adiabatic inversion recovery MAGNETIC RESONANCE IN MEDICINE Balchandani, P., Spielman, D. 2008; 59 (5): 980-988

  Abstract

  Proton magnetic resonance spectroscopic imaging ((1)H MRSI) at 7T offers many advantages, including increased SNR and spectral resolution. However, technical difficulties associated with operating at high fields, such as increased B(1) and B(0) inhomogeneity, severe chemical shift localization error, and converging T(1) values, make the suppression of the broad lipid peaks which can obscure targeted metabolite signals, particularly challenging. Conventional short tau inversion recovery can successfully suppress fat without restricting the selected volume, but only with significant metabolite signal loss. In this work, we have designed two new pulses for frequency-selective inversion recovery that achieve B(1)-insensitive fat suppression without degrading the signal from the major metabolites of interest. The first is a spectrally selective adiabatic pulse to be used in a volumetric (1)H MRSI sequence and the second is a spatial-spectral adiabatic pulse geared toward multi-slice (1)H MRSI. Partial interior volume selection may be used in addition to the pulses, to exclude areas with severe B(0) inhomogeneity. Some differences in the spectral profile as well as degree of suppression make each pulse valuable for different applications. 7T phantom and in vivo data show that both pulses significantly suppress fat, while leaving most of the metabolite signal intact.

  View details for DOI 10.1002/mrm.21537

  View details for Web of Science ID 000255230700006

  View details for PubMedID 18429027

  View details for PubMedCentralID PMC2724983

• Interleaved narrow-band PRESS sequence with adiabatic spatial-spectral refocusing pulses for H-1 MRSI at 7T MAGNETIC RESONANCE IN MEDICINE Balchandani, P., Pauly, J., Spielman, D. 2008; 59 (5): 973-979

  Abstract

  Proton magnetic resonance spectroscopic imaging ((1)H MRSI) is a useful technique for measuring metabolite levels in vivo, with Choline (Cho), Creatine (Cre), and N-Acetyl-Aspartate (NAA) being the most prominent MRS-detectable brain biochemicals. (1)H MRSI at very high fields, such as 7T, offers the advantages of higher SNR and improved spectral resolution. However, major technical challenges associated with high-field systems, such as increased B(1) and B(0) inhomogeneity as well as chemical shift localization (CSL) error, degrade the performance of conventional (1)H MRSI sequences. To address these problems, we have developed a Position Resolved Spectroscopy (PRESS) sequence with adiabatic spatial-spectral (SPSP) refocusing pulses, to acquire multiple narrow spectral bands in an interleaved fashion. The adiabatic SPSP pulses provide magnetization profiles that are largely invariant over the 40% B(1) variation measured across the brain at 7T. Additionally, there is negligible CSL error since the transmit frequency is separately adjusted for each spectral band. in vivo (1)H MRSI data were obtained from the brain of a normal volunteer using a standard PRESS sequence and the interleaved narrow-band PRESS sequence with adiabatic refocusing pulses. In comparison with conventional PRESS, this new approach generated high-quality spectra from an appreciably larger region of interest and achieved higher overall SNR.

  View details for DOI 10.1002/mrm.21539

  View details for Web of Science ID 000255230700005

  View details for PubMedID 18429014

  View details for PubMedCentralID PMC2692522

• Slice-selective tunable-flip adiabatic low peak-power excitation pulse MAGNETIC RESONANCE IN MEDICINE Balchandani, P., Pauly, J., Spielman, D. 2008; 59 (5): 1072-1078

  Abstract

  Adiabatic pulses are useful in achieving uniform excitation profiles in the presence of B(1)-inhomogeneity. At higher fields, this inhomogeneity becomes more severe, further amplifying the need for B(1)-insensitive excitation. Although gradient modulation techniques for slice-selective adiabatic excitation have been introduced, a pulse that falls within the gradient and RF amplifier limits for most commercial human scanners is currently unavailable. In this work, we present an alternative gradient modulated approach for pulse design that achieves adiabatic slice selection with significantly lower RF peak power requirements. The resulting Slice-selective Tunable-flip AdiaBatic Low peak-power Excitation (STABLE) pulse consists of an oscillating gradient in conjunction with a BIR-4-like RF envelope that is sampled by many short spatial subpulses to achieve spatial selectivity. Simulations show that the expected spatial profile as well as the off-resonance behavior of the pulse remain invariant for a range of B(1) values. Phantom and in vivo results demonstrate the adiabaticity and slice selectivity of the STABLE pulse.

  View details for DOI 10.1002/mrm.21540

  View details for Web of Science ID 000255230700017

  View details for PubMedID 18429017

  View details for PubMedCentralID PMC2692433

• Prospective neurochemical characterization of child offspring of parents with bipolar disorder 63rd Annual Convention of the Society-of-Biological-Psychiatry Singh, M. K., Chang, K. D., Spielman, D. M. ELSEVIER SCIENCE INC. 2008: 191S–191S

  View details for Web of Science ID 000254163700610

• Fast parallel spiral chemical shift imaging at 3T using iterative SENSE reconstruction MAGNETIC RESONANCE IN MEDICINE Mayer, D., Kim, D., Spielman, D. M., Bammer, R. 2008; 59 (4): 891-897

  Abstract

  Spiral chemical shift imaging (CSI) is a fast CSI technique that simultaneously encodes 1D spectral and 2D spatial information. Therefore, it potentially allows one to perform a 2D-CSI experiment in a single shot. However, for most applications, limitations on maximum gradient strength and slew rate make multiple excitations necessary in order to achieve a desired spectral bandwidth. In this work we reduce the number of spatial interleaves and, hence, the minimum total measurement time of spiral CSI by using an iterative sensitivity encoding reconstruction algorithm which utilizes complementary spatial encoding afforded by the spatially inhomogeneous sensitivity profiles of individual receiver coils. The performance of the new method was evaluated in phantom and in vivo experiments. Parallel spiral CSI produced maps of brain metabolites similar to those obtained using conventional gridding reconstruction of the fully sampled data with only a small decrease in time-normalized signal-to-noise ratio and a small increase in noise for higher acceleration factors.

  View details for DOI 10.1002/mrm.21572

  View details for Web of Science ID 000254645500027

  View details for PubMedID 18383298

• SENSE phase-constrained magnitude reconstruction with iterative phase refinement MAGNETIC RESONANCE IN MEDICINE Lew, C., Pineda, A. R., Clayton, D., Spielman, D., Chan, F., Bammer, R. 2007; 58 (5): 910-921

  Abstract

  Conventional sensitivity encoding (SENSE) reconstruction is based on equations in the complex domain. However, for many MRI applications only the magnitude is relevant. If there exists an estimate of the underlying phase information, a magnitude-only phase-constrained reconstruction can help to improve the conditioning of the SENSE reconstruction problem. Consequently, this reduces g-factor-related noise enhancement. In previous attempts at phase-constrained SENSE reconstruction, image quality was hampered by strong aliasing artifacts resulting from inadequate phase estimates and high sensitivity to phase errors. If a full-resolution phase image is used, a significant reduction in aliasing errors and better noise properties compared to SENSE can be obtained. An iterative scheme that improves the phase estimate to better approximate the phase is presented. The mathematical framework of the new approach is provided together with comparisons of conventional SENSE, phase-constrained SENSE, and the new phase-refinement method. Both theory and experimental verification demonstrate significantly better noise performance at high reduction factors, i.e., close to the theoretical limit. For applications that need only magnitude data, an iterative phase-constrained SENSE reconstruction can provide substantial SNR improvement over SENSE reconstruction and less artifacts than phase-constrained SENSE.

  View details for DOI 10.1002/mrm.21284

  View details for Web of Science ID 000250560000008

  View details for PubMedID 17969127

• Fast multivoxel two-dimensional spectroscopic imaging at 3 T MAGNETIC RESONANCE IMAGING Kim, D., Henry, R., Spielman, D. M. 2007; 25 (8): 1155-1161

  Abstract

  The utility of multivoxel two-dimensional chemical shift imaging in the clinical environment will ultimately be determined by the imaging time and the metabolite peaks that can be detected. Different k-space sampling schemes can be characterized by their minimum required imaging time. The use of spiral-based readout gradients effectively reduces the minimum scan time required due to simultaneous data acquisition in three k-space dimensions (k(x), k(y) and k(f(2))). A 3-T spiral-based multivoxel two-dimensional spectroscopic imaging sequence using the PRESS excitation scheme was implemented. Good performance was demonstrated by acquiring preliminary in vivo data for applications, including brain glutamate imaging, metabolite T(2) quantification and high-spatial-resolution prostate spectroscopic imaging. All protocols were designed to acquire data within a 17-min scan time at a field strength of 3 T.

  View details for DOI 10.1016/j.mri.2007.01.118

  View details for Web of Science ID 000250148700005

  View details for PubMedID 17418519

  View details for PubMedCentralID PMC2128753

• Optimization of fast spiral chemical shift imaging using least squares reconstruction: Application for hyperpolarized C-13 metabolic imaging MAGNETIC RESONANCE IN MEDICINE Levin, Y. S., Mayer, D., Yen, Y., Hurd, R. E., Spielman, D. M. 2007; 58 (2): 245-252

  Abstract

  A least-squares-based optimization and reconstruction algorithm has been developed for rapid metabolic imaging in the context of hyperpolarized (13)C. The algorithm uses a priori knowledge of resonance frequencies, J-coupling constants, and T(2)* values to enable acquisition of high-quality metabolic images with imaging times of approximately 100 ms for an 8-cm field of view (FOV) and 0.5 cm isotropic resolution. A root-mean-square error (rMSE) analysis is introduced to optimize metabolic image quality by appropriate choice of pulse sequence parameters, echo times, and signal model. By performing the reconstruction in k-space, the algorithm also allows the inclusion of the effect of chemical shift evolution during the readout period. Single-interleaf multiecho spiral chemical shift imaging (spCSI) is analyzed in detail as an illustrative example for the use of the new reconstruction and optimization algorithm. Simulation of the in vivo spectrum following the bolus injection of hyperpolarized (13)C(1) pyruvate shows that single-interleaf spiral spectroscopic imaging can achieve image quality in 100 ms, comparable to the performance of a 13-s phase-encoded chemical shift imaging (FIDCSI) experiment. Single-interleaf spCSI was also tested at a 3-T MR scanner using a phantom containing approximately 0.5-M solutions of alanine, lactate, and a pyruvate-pyruvate hydrate C(1)-C(2) ester at thermal equilibrium polarization, all enriched to 99% (13)C in the C(1) carbonyl positions. Upon reconstruction using the k-space-based least-squares technique, metabolite ratios obtained using the spCSI method were comparable to those obtained using a reference FIDCSI acquisition.

  View details for DOI 10.1002/mrm.21327

  View details for Web of Science ID 000248488300006

  View details for PubMedID 17654596

• RF refocused echoes of J-coupled spin systems: Effects on RARE-based spectroscopic imaging MAGNETIC RESONANCE IN MEDICINE Mayer, D., Dreher, W., Leibfritz, D., Spielman, D. M. 2007; 57 (5): 967-971

  Abstract

  A numerical simulation tool was developed to calculate the echo amplitudes of J-coupled resonances within a series of radiofrequency (RF) refocused echoes. The signal modulation due to J-coupling in rapid acquisition with relaxation enhancement (RARE) is suppressed only when the inverse of the pulse interval (tau) is large compared to both the chemical shift (CS) difference (Deltadelta) of the coupled spins and the coupling constant. In contrast, the echo amplitudes in ultrafast low-flip-angle RARE (U-FLARE) oscillate around a quasi-steady-state value that is greater than zero (neglecting relaxation and diffusion) even when Deltadelta > 1/tau. The flip-angle distribution over the measured slice caused by the use of Gaussian-shape slice-selective refocusing pulses further reduces the echo oscillations. When the pulse interval falls short of the fast pulse rate regime, spectroscopic U-FLARE provides an improved spatial impulse response in the phase-encoding (PE) direction compared to spectroscopic RARE.

  View details for DOI 10.1002/mrm.21206

  View details for Web of Science ID 000246052800019

  View details for PubMedID 17457878

• Peak velocity and flow quantification validation for sensitivity-encoded phase-contrast MR imaging ACADEMIC RADIOLOGY Lew, C. D., Alley, M. T., Bammer, R., Spielman, D. M., Chan, F. P. 2007; 14 (3): 258-269

  Abstract

  Phase-contrast (PC) magnetic resonance imaging (MRI) technique has important clinical applications in blood flow quantification and pressure gradient estimation by velocity measurement. Parallel imaging using sensitivity encoding (SENSE) may substantially reduce scan time. We demonstrate the utility of PC-MRI measurements accelerated by SENSE under clinical conditions.Accuracy and repeatability of a SENSE-PC implementation was evaluated by comparison with a commercial PC sequence with five normal volunteers. Twenty-six patients were then scanned with SENSE-PC at reduction factors (R = 1, 2, and 3). Blood flow and peak velocity were measured in the aorta and pulmonary trunk in 16 patients and peak velocity was measured at the coarctation of 10 patients. Quantitative flow, shunt ratio, and peak velocity measurements obtained with different reduction factors were compared using correlation, linear regression, and Bland-Altman statistics. All studies were approved by an Institutional Review Board, and informed consent was acquired from all subjects.The correlation coefficients for all comparisons were >0.962 and with high statistical significance (P < .01). Linear regression slopes ranged between 0.96 and 1.11 for flow and 0.88 to 1.05 for peak velocity. For flow, the Bland-Altman statistics yielded a total mean difference ranging from -0.02 to 0.05) L/minute with 2 standard of deviation limits ranging from -0.52 to 0.75 L/minute. For peak velocity, the total mean difference ranged from -0.10 to -0.004) milliseconds with 2-SD limits ranging from -0.062 to 0.46 milliseconds. R = 3 to R = 1 comparisons had greater 2-SD limits than R = 2 to R = 1 comparisons.SENSE PC-MRI measurements for flow and pressure gradient estimation were comparable to conventional PC-MRI.

  View details for DOI 10.1016/j.acra.2006.11.008

  View details for Web of Science ID 000246861100003

  View details for PubMedID 17307658

  View details for PubMedCentralID PMC1993829

• Lactate-base H-1 magnetic spectroscopy does not predict response and outcomes in patients with stage IV head and neck squamous cell carcinoma 49th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Le, Q., Koong, A., Lieskovsky, Y., Graves, E., PINTO, H., Brown, J., Spielman, D. ELSEVIER SCIENCE INC. 2007: S200–S201

  View details for Web of Science ID 000249950200352

• Fast metabolic imaging of systems with sparse spectra: Application for hyperpolarized C-13 imaging MAGNETIC RESONANCE IN MEDICINE Mayer, D., Levin, Y. S., Hurd, R. E., Glover, G. H., Spielman, D. M. 2006; 56 (4): 932-937

  Abstract

  A fast spiral chemical shift imaging (spCSI) sequence was developed for application to hyperpolarized (13)C imaging. The sequence exploits sparse spectra, which can occur in such applications, and prior knowledge of resonance frequencies to reduce the measurement time by undersampling the data in the spectral domain. As a consequence, multiple reconstructions of a given data set have to be computed in which only components with frequencies within a certain bandwidth are reconstructed "in focus" while others are severely blurred ("spectral tomosynthesis"). The sequence was tested at 3 T on a phantom containing approximately 1.5-M solutions of alanine (Ala), lactate (Lac), and pyruvate-pyruvate hydrate C1-C2 ester (with two resonances, PPE1 and PPE2) at thermal equilibrium polarization, all enriched to 99% (13)C in the C1 carbonyl positions. Results from spCSI with a single spatial interleaf (single-shot spCSI) and three interleaves (three-shot spCSI) were compared with those obtained by phase-encoded free induction decay CSI (FIDCSI). The metabolic maps of all four resonances for three-shot spCSI, and of PPE1 and PPE2 for single-shot spCSI demonstrate resolution and localization properties similar to those of the FIDCSI images. The metabolic maps of Ala and Lac for single-shot spCSI contain minor artifacts due to signal overlap of aliased resonances.

  View details for DOI 10.1002/mrm.21025

  View details for Web of Science ID 000240897000028

  View details for PubMedID 16941617

• Reducing gradient imperfections for spiral magnetic resonance spectroscopic imaging MAGNETIC RESONANCE IN MEDICINE Kim, D., Spielman, D. M. 2006; 56 (1): 198-203

  Abstract

  Spiral k-space magnetic resonance spectroscopic imaging (MRSI) requires high performance from gradient hardware systems. During the readout phase, oscillating gradients are continuously played out, which can cause undesired effects. These effects on the quality of SI data are non-intuitive because of their time-varying nature. In this work we describe the effects of undesirable gradient performance on SI. Measurements of the true readout trajectories were performed and the results were then used in the reconstruction process. The effects of these imperfections resulted in a spatially and spectrally varying amplitude and frequency modulation. The use of the measured trajectories in the reconstruction process yielded an up to 20% increase in signal amplitude recovery.

  View details for DOI 10.1002/mrm.20928

  View details for Web of Science ID 000238823600021

  View details for PubMedID 16724300

• Fast CT-PRESS-based spiral chemical shift imaging at 3 Tesla MAGNETIC RESONANCE IN MEDICINE Mayer, D., Kim, D. H., Adalsteinsson, E., Spielman, D. M. 2006; 55 (5): 974-978

  Abstract

  A new sequence is presented that combines constant-time point-resolved spectroscopy (CT-PRESS) with fast spiral chemical shift imaging. It allows the acquisition of multivoxel spectra without line splitting with a minimum total measurement time of less than 5 min for a field of view of 24 cm and a nominal 1.5x1.5-cm2 in-plane resolution. Measurements were performed with 17 CS encoding steps in t1 (Deltat1=12.8 ms) and an average echo time of 151 ms, which was determined by simulating the CT-PRESS experiment for the spin systems of glutamate (Glu) and myo-inositol (mI). Signals from N-acetyl-aspartate, total creatine, choline-containing compounds (Cho), Glu, and mI were detected in a healthy volunteer with no or only minor baseline distortions within 14 min on a 3 T MR scanner.

  View details for DOI 10.1002/mrm.20853

  View details for Web of Science ID 000237151600002

  View details for PubMedID 16586451

• Metabolite ratios measured by proton magnetic resonance spectroscopy correlate with postmenstrual age in very low birth weight preterm infants with normal neuromotor and Bayley results. Western Regional Meeting of the American-Federation-for-Medical-Research Van Brussel, E. M., Mirmiran, M., Spielman, D. M., Barnes, P. D., Sutcliffe, T. L., Dermon, J. D., Ariagno, R. L. LIPPINCOTT WILLIAMS & WILKINS. 2006: S97–S97

  View details for Web of Science ID 000235301500117

• Proton magnetic resonance spectroscopy at term age is not predictive of neurodevelopmental outcome in very low birth weight preterm infants. Van Brusssel, E. M., Mirmiran, M., Spielman, D. M., Barnes, P. D., Sutcliffe, T. L., Dermon, J. D., Ariagno, R. L. B C DECKER INC. 2006: S128

  View details for Web of Science ID 000235301500292

• Dose-dependent effects of tin mesoporphyrin on heme oxygenase activity inhibition in newborn mice. Western Regional Meeting of the American-Federation-for-Medical-Research Morioka, I., Wong, R. J., Vreman, H. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2006: S128–S128

  View details for Web of Science ID 000235301500293

• N-acetylaspartate levels in bipolar offspring with and at high-risk for bipolar disorder BIPOLAR DISORDERS Gallelli, K. A., Wagner, C. M., Karchemskiy, A., Howe, M., Spielman, D., Reiss, A., Chang, K. D. 2005; 7 (6): 589-597

  Abstract

  Studies have reported decreased N-acetylaspartate (NAA) in dorsolateral prefrontal cortex (DLPFC) of adults and children with bipolar disorder (BD), suggesting decreased neuronal density in this area. However, it is unclear if this finding represents neurodegeneration after or a trait marker present before BD onset. To address this question, we used proton magnetic resonance spectroscopy ((1)H-MRS) to compare DLPFC levels of NAA among bipolar offspring with early-onset BD, bipolar offspring with subsyndromal symptoms of BD and healthy children.Participants were 9-18 years old, and included 60 offspring of parents with bipolar I or II disorder (32 with BD and 28 with subsyndromal symptoms of BD), and 26 healthy controls. (1)H-MRS at 3 T was used to study 8-cm(3) voxels placed in left and right DLPFC.There were no significant group differences in mean right or left DLPFC NAA/Cr ratios. Exploratory analyses of additional metabolites (myoinositol, choline) also yielded no significant group differences. NAA/Cr ratios were not correlated with age, duration of illness, or exposure to lithium or valproate.Our findings suggest that DLPFC NAA/Cr ratios cannot be used as a trait marker for BD. Although we did not find decreased DLPFC NAA/Cr ratios in children and adolescents with BD, it is still possible that such levels begin to decrease after longer durations of illness into adulthood. Longitudinal neuroimaging studies of patients with BD accounting for developmental and treatment factors are needed to further clarify the neurodegenerative aspects of BD.

  View details for PubMedID 16403184

• Prefrontal neurometabolite changes following lamotrigine treatment in adolescents with bipolar depression 44th Annual Meeting of the American-College-Neuropsychopharmacology Chang, K. K., Gallelli, K., Howe, M., Saxena, K., Wagner, C., Spielman, D., Reiss, A. NATURE PUBLISHING GROUP. 2005: S102–S103

  View details for Web of Science ID 000233442100277

• Stroke volume and cardiac output in juvenile elephant seals during forced dives JOURNAL OF EXPERIMENTAL BIOLOGY Thornton, S. J., Hochachka, P. W., Crocker, D. E., Costa, D. P., LeBoeuf, B. J., Spielman, D. M., Pelc, N. J. 2005; 208 (19): 3637-3643

  Abstract

  The aim of this study was to examine the effect of forced diving on cardiac dynamics in a diving mammal by evaluating cardiac output and heart rate. We used MR Imaging and phase contrast flow analysis to obtain accurate flow measurements from the base of the aorta. Heart rate (fh) and cardiac output (Q) were measured before, during and after dives in four restrained juvenile northern elephant seals, Mirounga angustirostris, and stroke volume (Vs) was calculated (Vs=Q/fh). Mean Q during diving (4011+/-387 ml min(-1)) and resting (6530+/-1018 ml min(-1)) was not significantly different (paired t-test; P<0.055). Diving was accompanied by a 20% increase in Vs over the pre-dive level. Pre-dive, post-dive or diving fh was not significantly correlated with Vs during any state. Diving Vs correlated negatively with the bradycardic ratio (diving fh to pre-dive fh). In this study, the degree of bradycardia during diving was less than in previous pinniped studies, suggesting that the reduction in vagal input may contribute to the observed increase in Vs.

  View details for DOI 10.1242/jeb.01789

  View details for Web of Science ID 000233127200011

  View details for PubMedID 16169941

• Estimation of renal extraction fraction based on postcontrast venous and arterial differential T-1 values: An error analysis MAGNETIC RESONANCE IN MEDICINE Levin, Y. S., Chow, L. C., Pec, N. J., Sommer, F. G., Spielman, D. M. 2005; 54 (2): 309-316

  Abstract

  An error analysis for quantifying single kidney extraction fraction (EF) via differential T1 measurements in the renal vein (RV) and renal artery (RA) is presented. Sources of error include blood flow effects, the effect of a short repetition time (TR), and the impact of uncertainties in the T1 estimates on the final EF calculations. Blood flow effects were investigated via simulation. For a range of blood velocities in the renal vein that may be found in kidney disease, incomplete refreshment of blood between readouts results in significant errors in T1 estimation. For a .5-cm slice, 110-ms sampling interval, and T1 of 600 ms, T1 estimation to within 5% of true T1 requires an average through-plane velocity of 6.75 cm/s for parabolic flow, and 3.5 cm/s for plug flow. Improvement can be achieved by accurately estimating the fraction of blood that has not refreshed between readouts (f(old)), while the quality of the T1 estimate varies with the accuracy of f(old) estimation. Shortening of the TR was investigated using phantom and in vivo studies. T1 was estimated to within 3% of the true value on phantoms, and within 5% of the true value for flowing blood for TR = 2T1. The estimated EF is shown to be very sensitive to the difference between T(1RA) and T(1RV). To achieve 10% or 20% uncertainty in the EF estimate, T1 in the renal vein and renal artery must be estimated to within approximately 1% or 2%. Because of limitations on measurement accuracy and precision, this method appears to be impractical at this time.

  View details for Web of Science ID 000230765700008

  View details for PubMedID 16032662

• Detection of glutamate in the human brain at 3 T using optimized constant time point resolved spectroscopy MAGNETIC RESONANCE IN MEDICINE Mayer, D., Spielman, D. M. 2005; 54 (2): 439-442

  Abstract

  A CT-PRESS sequence was implemented on a 3-T MR scanner and optimized for the detection of the C4 resonance of glutamate. By simulating the sequence using the full density matrix it was found that 121 chemical shift encoding steps in t1 with an increment delta t1 = 1.6 ms were sufficient to separate the glutamate C4 resonance. The simulations also showed that the highest signal-to-noise ratio was achieved at an average echo time of 131 ms. When using an eightfold undersampling scheme in f1 in order to reduce the minimum total measurement time, the average echo time was 139 ms with 17 encoding steps (delta t1 = 12.8 ms). The sequence was tested on phantoms containing solutions of various brain metabolites and on healthy human volunteers. Besides resolving glutamate, other resonances detected in vivo comprised N-acetyl aspartate, total creatine, choline containing compounds, and myo-inositol. However, glutamine resonances could not be resolved due to severe signal overlap from glutamate and N-acetyl aspartate.

  View details for DOI 10.1002/mrm.20571

  View details for Web of Science ID 000230765700023

  View details for PubMedID 16032664

• Temporal lobe magnetic resonance spectroscopic imaging following amygdalohippocampectomy for treatment-resistant epilepsy selective ACTA NEUROLOGICA SCANDINAVICA Spencer, D. C., Szumowski, J., Kraemer, D. F., Wang, P. Y., Burchiel, K. J., Spielman, D. M. 2005; 112 (1): 6-12

  Abstract

  Magnetic resonance spectroscopic imaging (MRSI) may show circumscribed or extensive decreased brain N-acetyl aspartate (NAA)/creatine and phosphocreatine (Cr) in epilepsy patients. We compared temporal lobe MRSI in patients seizure-free (SzF) or with persistent seizures (PSz) following selective amygdalohippocampectomy (SAH) for medically intractable mesial temporal lobe epilepsy (mTLE). We hypothesized that PSz patients had more extensive temporal lobe metabolite abnormalities than SzF patients.MRSI was used to study six regions of interest (ROI) in the bilateral medial and lateral temporal lobes in 14 mTLE patients following SAH and 11 controls.PSz patients had more temporal lobe ROI with abnormally low NAA/Cr than SzF patients, including the unoperated hippocampus and ipsilateral lateral temporal lobe.Postoperative temporal lobe MRSI abnormalities are more extensive if surgical outcome following SAH is poor. MRSI may be a useful tool to improve selection of appropriate candidates for SAH by identifying patients requiring more intensive investigation prior to epilepsy surgery. Future prospective studies are needed to evaluate the utility of MRSI, a predictor of successful outcome following SAH.

  View details for DOI 10.1111/j.1600-0404.2005.00439.x

  View details for PubMedID 15932349

• In vivo prostate magnetic resonance spectroscopic imaging using two-dimensional J-resolved PRESS at 3 T MAGNETIC RESONANCE IN MEDICINE Kim, D. H., Margolis, D., Xing, L., Daniel, B., Spielman, D. 2005; 53 (5): 1177-1182

  Abstract

  In vivo magnetic resonance spectroscopic imaging of the prostate using single-voxel and multivoxel two-dimensional (2D) J-resolved sequences is investigated at a main magnetic field strength of 3 T. Citrate, an important metabolite often used to aid the detection of prostate cancer in magnetic resonance spectroscopic exams, can be reliably detected along with the other metabolites using this method. We show simulations and measurements of the citrate metabolite using 2D J-resolved spectroscopy to characterize the spectral pattern. Furthermore, using spiral readout gradients, the single-voxel 2D J-resolved method is extended to provide the spatial distribution information as well all within a reasonable scan time (17 min). Phantom and in vivo data are presented to illustrate the multivoxel 2D J-resolved spiral chemical shift imaging sequence.

  View details for DOI 10.1002/mrm.20452

  View details for Web of Science ID 000228796900026

  View details for PubMedID 15844143

• Mapping of the prostate in endorectal coil-based MRI/MRSI and CT: A deformable registration and validation study 45th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Lian, J., Xing, L., Hunjan, S., Dumoulin, C., Levin, J., Lo, A., Watkins, R., Rohling, K., Giaquinto, R., Kim, D., Spielman, D., Daniel, B. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2004: 3087–94

  Abstract

  The endorectal coil is being increasingly used in magnetic resonance imaging (MRI) and MR spectroscopic imaging (MRSI) to obtain anatomic and metabolic images of the prostate with high signal-to-noise ratio (SNR). In practice, however, the use of endorectal probe inevitably distorts the prostate and other soft tissue organs, making the analysis and the use of the acquired image data in treatment planning difficult. The purpose of this work is to develop a deformable image registration algorithm to map the MRI/MRSI information obtained using an endorectal probe onto CT images and to verify the accuracy of the registration by phantom and patient studies. A mapping procedure involved using a thin plate spline (TPS) transformation was implemented to establish voxel-to-voxel correspondence between a reference image and a floating image with deformation. An elastic phantom with a number of implanted fiducial markers was designed for the validation of the quality of the registration. Radiographic images of the phantom were obtained before and after a series of intentionally introduced distortions. After mapping the distorted phantom to the original one, the displacements of the implanted markers were measured with respect to their ideal positions and the mean error was calculated. In patient studies, CT images of three prostate patients were acquired, followed by 3 Tesla (3 T) MR images with a rigid endorectal coil. Registration quality was estimated by the centroid position displacement and image coincidence index (CI). Phantom and patient studies show that TPS-based registration has achieved significantly higher accuracy than the previously reported method based on a rigid-body transformation and scaling. The technique should be useful to map the MR spectroscopic dataset acquired with ER probe onto the treatment planning CT dataset to guide radiotherapy planning.

  View details for DOI 10.1118/1.106292

  View details for Web of Science ID 000225372300019

  View details for PubMedID 15587662

• Spiral readout gradients for the reduction of motion artifacts in chemical shift imaging MAGNETIC RESONANCE IN MEDICINE Kim, D. H., Adalsteinsson, E., Spielman, D. M. 2004; 51 (3): 458-463

  Abstract

  A motion artifact reduction method for proton chemical shift imaging (CSI) is presented. The method uses spiral-based readout gradients for data acquisition. A characteristic of spiral-based readout gradients is that data are repeatedly sampled at the kxy origin. These data points are used to estimate and correct for motion-induced phase variations. Both phantom and in vivo spectra reconstructed using the new motion artifact reduction algorithm showed significant signal-to-noise ratio (SNR) improvements as compared to uncorrected data.

  View details for DOI 10.1002/mrm.20004

  View details for Web of Science ID 000220003200005

  View details for PubMedID 15004785

• Using finite-element method to register endorectal coil-based MRI/MRSI with treatment planning CT images 46th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Schreibmann, E., Kim, D., Hancock, S. L., Boyer, A., Spielman, D., Daniel, B., Xing, L. ELSEVIER SCIENCE INC. 2004: S592–S593

  View details for Web of Science ID 000223854700770

• Quality assurance of magnetic resonance spectroscopic imaging-derived metabolic data 44th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Hunjan, S., Adalsteinsson, E., Kim, D. H., Harsh, G. R., Boyer, A. L., Spielman, D., Xing, L. ELSEVIER SCIENCE INC. 2003: 1159–73

  Abstract

  Spatially resolved metabolite maps, as measured by magnetic resonance spectroscopic imaging (MRSI) methods, are being increasingly used to acquire metabolic information to guide therapy, with metabolite ratio maps perhaps providing the most diagnostic information. We present a quality assurance procedure for MRSI-derived metabolic data acquired ultimately for guiding conformal radiotherapy.An MRSI phantom filled with brain-mimicking solutions was custom-built with an insert holding eight vials containing calibration solutions of precisely varying metabolite concentrations that emulated increasing grade/density of brain tumor. Phantom metabolite ratios calculated from fully relaxed 1D, 2D, and 3D MRS data for each vial were compared with calibrated metabolite ratios acquired at 9.4 T. Additionally, 3D ratio maps were "discretized" to eight pseudoabnormality levels on a slice-by-slice basis and the accuracy of this procedure was verified.Regression analysis revealed expected linear relationships between experimental and calibration metabolite ratios with intercepts close to zero for the three acquisition modes. 1D MRS data agreed most with theoretical considerations (regression coefficient, b = 0.969; intercept 0.008). The 2D (b = 1.049; intercept -0.199) and 3D (correlation coefficient r(2) = 0.9978-0.7336 for five slices) MRSI indicated reduced MRS data quality in regions of degraded B(0) and B(1) homogeneity. Pseudoabnormality levels were found to be consistent with expectations within regions of adequate B(0) homogeneity.This simple phantom-based approach to generate baseline calibration curves for all MRS acquisition modes may be useful to identify temporal deviations from acceptable data quality in a routine clinical environment or for testing new MRS and MRSI acquisition software.

  View details for DOI 10.1016/S0630-3016(03)01564-5

  View details for Web of Science ID 000186293800031

  View details for PubMedID 14575849

• Simple analytic variable density spiral design MAGNETIC RESONANCE IN MEDICINE Kim, D. H., Adalsteinsson, E., Spielman, D. M. 2003; 50 (1): 214-219

  Abstract

  Variable density spirals have been proposed in a variety of applications, including MR fluoroscopy, cardiac imaging, and MR spectroscopic imaging. In this work, a simple analytic solution for designing a flexible set of variable density spiral trajectory waveforms is presented. The method enables real-time waveform prescription on scanners with limited computational power. Both slew rate-limited and amplitude-limited regimes are incorporated in the design process.

  View details for DOI 10.1002/mrm.10493

  View details for Web of Science ID 000183961800029

  View details for PubMedID 12815699

• Quality assurance for MR spectroscopic imaging-guided prostate therapy 45th Annual Meeting of the American-Association-of-Physicists-in-Medicine Hunjan, S., Kim, D., Adalsteinsson, E., Daniel, B., Dumoulin, C., Boyer, A., Spielman, D., Xing, L. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2003: 1454–54

  View details for Web of Science ID 000183658500583

• Including metabolic uncertainty into proton MR spectroscopic imaging (MRSI)-guided inverse treatment planning 45th Annual Meeting of the American-Association-of-Physicists-in-Medicine Lian, J., Spielman, D., Cotrutz, C., Hunjan, S., Adalsteinsson, E., King, C., Luxton, G., Boyer, A., Kim, D., Daniel, B., Xing, L. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2003: 1384–84

  View details for Web of Science ID 000183658500279

• MRS in relation to hippocampal volume in the oldest old NEUROLOGY Spencer, D. C., Zitzelberger, T., Spielman, D., Kaye, J. 2003; 60 (7): 1194-1196

  Abstract

  The MRS brain metabolite ratio N-acetylaspartate (NAA)/myo-inositol (mI) is reported to be decreased in AD. MRS was used to study medial temporal and parietal regions in 60 cognitively healthy subjects older than 85 years. Subjects with small hippocampal volumes, a putative risk factor for dementia, had significantly lower NAA/mI in parietal and temporal lobes compared with other subjects. Neuropsychological tests and APOE genotype did not correlate with MRS ratios. MRS measures are candidate biomarkers for dementia risk.

  View details for PubMedID 12682335

• Low N-acetyl-aspartate and high choline in the anterior cingulum of recently abstinent methamphetamine-dependent subjects: a preliminary proton MRS study PSYCHIATRY RESEARCH-NEUROIMAGING Nordahl, T. E., Salo, R., Possin, K., Gibson, D. R., Flynn, N., Leamon, M., Galloway, G. P., Pfefferbaum, A., Spielman, D. M., Adalsteinsson, E., SULLIVAN, E. V. 2002; 116 (1-2): 43-52

  Abstract

  Studies based on animal models report that methamphetamine (MA) abuse diminishes dopamine (DA) and serotonin innervation in frontal brain regions. In this in vivo human study, we used proton magnetic resonance spectroscopy (MRS), which yields measures of N-acetyl-aspartate (NAA), a marker of living neurons, to examine frontal brain regions possibly affected by methamphetamine dependence (MD). We tested the hypothesis that MD subjects would exhibit abnormally low levels of NAA, referenced to creatine (Cr), in anterior cingulate gray matter. We further hypothesized that the primary visual cortex, which receives relatively less DA innervation than the frontal brain regions, would show normal NAA/Cr ratios in MD subjects. Subjects included nine MD men (mean+/-standard deviation (S.D.)=32.5+/-6.4 years) and nine age-matched control men (mean+/-S.D.=32.7+/-6.8 years). The MD subjects were MA-free for 4-13 weeks. Proton MRS metabolites were expressed as ratios of creatine; the absolute values of which did not distinguish controls and MD subjects. With regard to metabolite ratios, the MD men had significantly lower NAA/Cr in the cingulum (mean+/-standard error (S.E.): control=1.46+/-0.03; MD=1.30+/-0.03; Mann-Whitney P=0.01) but not in the visual cortex (mean+/-S.E.: control=1.64+/-0.06; MD=1.69+/-11; Mann-Whitney P=0.52) relative to controls. These results provide evidence for NAA/Cr deficit that is selective to the anterior cingulum, at least with respect to visual cortex, in MD subjects. The neuronal compromise that these changes reflect may contribute to the attentional deficits and dampened reward system in MD.

  View details for Web of Science ID 000179601500004

• Low N-acetyl-aspartate and high choline in the anterior cingulum of recently abstinent methamphetamine-dependent subjects: a preliminary proton MRS study. Magnetic resonance spectroscopy. Psychiatry research Nordahl, T. E., Salo, R., Possin, K., Gibson, D. R., Flynn, N., Leamon, M., Galloway, G. P., Pfefferbaum, A., Spielman, D. M., Adalsteinsson, E., Sullivan, E. V. 2002; 116 (1-2): 43-52

  Abstract

  Studies based on animal models report that methamphetamine (MA) abuse diminishes dopamine (DA) and serotonin innervation in frontal brain regions. In this in vivo human study, we used proton magnetic resonance spectroscopy (MRS), which yields measures of N-acetyl-aspartate (NAA), a marker of living neurons, to examine frontal brain regions possibly affected by methamphetamine dependence (MD). We tested the hypothesis that MD subjects would exhibit abnormally low levels of NAA, referenced to creatine (Cr), in anterior cingulate gray matter. We further hypothesized that the primary visual cortex, which receives relatively less DA innervation than the frontal brain regions, would show normal NAA/Cr ratios in MD subjects. Subjects included nine MD men (mean+/-standard deviation (S.D.)=32.5+/-6.4 years) and nine age-matched control men (mean+/-S.D.=32.7+/-6.8 years). The MD subjects were MA-free for 4-13 weeks. Proton MRS metabolites were expressed as ratios of creatine; the absolute values of which did not distinguish controls and MD subjects. With regard to metabolite ratios, the MD men had significantly lower NAA/Cr in the cingulum (mean+/-standard error (S.E.): control=1.46+/-0.03; MD=1.30+/-0.03; Mann-Whitney P=0.01) but not in the visual cortex (mean+/-S.E.: control=1.64+/-0.06; MD=1.69+/-11; Mann-Whitney P=0.52) relative to controls. These results provide evidence for NAA/Cr deficit that is selective to the anterior cingulum, at least with respect to visual cortex, in MD subjects. The neuronal compromise that these changes reflect may contribute to the attentional deficits and dampened reward system in MD.

  View details for PubMedID 12426033

• Inverse planning for functional image-guided intensity-modulated radiation therapy PHYSICS IN MEDICINE AND BIOLOGY Xing, L., Cotrutz, C., Hunjan, S., Boyer, A. L., Adalsteinsson, E., Spielman, D. 2002; 47 (20): 3567-3578

  Abstract

  Radiation therapy is an image-guided process whose success critically depends on the imaging modality used for treatment planning and the level of integration of the available imaging information. In this work, we establish a dose optimization framework for incorporating metabolic information from functional imaging modalities into the intensity-modulated radiation therapy (IMRT) inverse planning process and to demonstrate the technical feasibility of planning deliberately non-uniform dose distributions in accordance with functional imaging data. For this purpose, a metabolic map from functional images is discretized into a number of abnormality levels (ALs) and then fused with CT images. To escalate dose to the metabolically abnormal regions, we assume, for a given spatial point, a linear relation between the AL and the prescribed dose. But the formalism developed here is independent of the assumption and any other relation between AL and prescription is applicable. For a given AL and prescription relation, it is only necessary to prescribe the dose to the lowest AL in the target and the desired doses to other regions with higher AL values are scaled accordingly. To accomplish differential sparing of a sensitive structure when its functional importance (FI) distribution is known, we individualize the tolerance doses of the voxels within the structure according to their Fl levels. An iterative inverse planning algorithm in voxel domain is used to optimize the system with in homogeneous dose prescription. To model intra-structural trade-off, a mechanism is introduced through the use of voxel-dependent weighting factors, in addition to the conventional structure specific weighting factors which model the inter-structural trade-off. The system is used to plan a phantom case with a few hypothetical functional distributions and a brain tumour treatment with incorporation of magnetic resonance spectroscopic imaging data. The results indicated that it is technically feasible to produce deliberately non-uniform dose distributions according to the functional imaging requirements. Integration of functional imaging information into radiation therapy dose optimization allows for consideration of patient-specific biologic information and provides a significant opportunity to truly individualize radiation treatment. This should enhance our capability to safely and intelligently escalate dose and lays the technical foundation for future clinical studies of the efficacy of functional imaging-guided IMRT.

  View details for Web of Science ID 000179171900003

  View details for PubMedID 12433120

• Regularized higher-order in vivo shimming MAGNETIC RESONANCE IN MEDICINE Kim, D. H., Adalsteinsson, E., Glover, G. H., Spielman, D. M. 2002; 48 (4): 715-722

  Abstract

  A regularized algorithm is presented for localized in vivo shimming. The technique uses first- (X,Y,Z), second- (Z(2), ZX, ZY, X(2)-Y(2), XY), and third-order (Z(3)) shim coils, and is robust when applied to arbitrarily-shaped, as well as off-center, regions of interest (ROIs). A single-shot spiral pulse sequence is used for rapid field map acquisition, and a least-squares calculation of the shim currents is performed to minimize the root-mean-square (RMS) value of the B(0) inhomogeneity over a user-selected ROI. The use of a singular value decomposition (SVD) in combination with a regularization algorithm significantly improves the numerical stability of the least-squares fitting procedure. The fully automated shimming package is implemented on a 3 T GE Signa system and its robust performance is demonstrated in phantom and in vivo studies.

  View details for DOI 10.1002/mrm.10267

  View details for Web of Science ID 000178361000019

  View details for PubMedID 12353290

• Inverse planning for functional imaging-guided IMRT Xing, L., Hunjan, S., Cotruz, C., Yang, Y., Boyer, A., Adalsteinsson, E., Spielman, D. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2002: 1285–85

  View details for Web of Science ID 000176373400453

• Quality assurance of magnetic resonance Spectroscopic Imaging-guided radiation therapy Hunjan, S., Spielman, D., Adalsteinsson, E., Boyer, A., Xing, L. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2002: 1320–20

  View details for Web of Science ID 000176373400611

• Implementation of magnetic resonance spectroscopic imaging guided IMRT Hunjan, S., Spielman, D., Cotrutz, C., Adalsteinsson, E., Boyer, A., Xing, L. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2002: 1284–85

  View details for Web of Science ID 000176373400452

• 3 Tesla 1h-magnetic resonance spectroscopic measurements of prefrontal cortical gamma-aminobutyric acid (GABA) levels in bipolar disorder patients and healthy volunteers Wang, P. W., Dieckmann, N., Sailasuta, N., Adalsteinsson, E., Spielman, D., Ketter, T. A. ELSEVIER SCIENCE INC. 2002: 197S–197S

  View details for Web of Science ID 000174980400553

• Noninvasive measurement of extraction fraction and single-kidney glomerular filtration rate with MR imaging in swine with surgically created renal artery stenoses RADIOLOGY Coulam, C. H., Lee, J. H., Wedding, K. L., Spielman, D. M., Pelc, N. J., Kee, S. T., Hill, B. B., Bouley, D. M., Derby, G. C., Myers, B. D., Sawyer-Glover, A. M., Sommer, F. G. 2002; 223 (1): 76-82

  Abstract

  To test whether magnetic resonance (MR) imaging enables accurate measurement of extraction fraction (EF) in swine with unilateral renal ischemia and to evaluate effects of renal arterial stenosis on EF and single-kidney glomerular filtration rate.High-grade unilateral renal arterial stenoses were surgically created in eight pigs. Direct measurements of renal venous and arterial inulin concentration provided reference standard estimates of single-kidney EF. Pigs were imaged with a 1.5-T imager to estimate EF, renal blood flow, and glomerular filtration rate. A breath-hold inversion-recovery spiral sequence was used to measure T1 of blood in the infrarenal inferior vena cava and renal veins after intravenous administration of gadopentetate dimeglumine, and these data were used to calculate EF. Cine-phase contrast material-enhanced imaging of the renal arteries provided quantitative renal blood flow measurements. Bilateral single-kidney glomerular filtration rate was then determined: glomerular filtration rate = renal blood flow x (1 - hematocrit level) x EF.A statistically significant linear correlation was found between EF, as determined with MR imaging, and inulin (r = 0.77). As compared with kidneys without renal arterial stenosis, kidneys with renal arterial stenosis showed 50% (0.14/0.28) EF reduction (P <.01) and 59% glomerular filtration rate reduction (P <.01).MR imaging shows promise for in vivo measurement of EF and glomerular filtration rate, which may be useful in assessing the clinical importance of renal arterial stenosis.

  View details for DOI 10.1148/radiol.2231010420

  View details for PubMedID 11930050

• N-acetylaspartate - A marker of neuronal integrity ANNALS OF NEUROLOGY SULLIVAN, E. V., Adalsteinsson, E., Spielman, D. M., Hurd, R. E., Pfefferbaum, A. 2001; 50 (6): 823-823

  View details for Web of Science ID 000172410900022

  View details for PubMedID 11761485

• Zero-quantum filter offering single-shot lipid suppression and simultaneous detection of lactate, choline, and creatine resonances MAGNETIC RESONANCE IN MEDICINE Star-Lack, J. M., Spielman, D. M. 2001; 46 (6): 1233-1237

  Abstract

  A zero-quantum (ZQ) filter offering single-shot lipid suppression and providing for simultaneous detection of the lactate methyl doublet (1.3 ppm) and nonoverlapping singlets including choline (Cho, 3.2 ppm) and creatine (Cr, 3.0 ppm) is described. Filtering is provided by soft mixing and reading pulses (RF(mix), RF(rd)) that are selective for the lactate methine quartet (4.1 ppm), Cho, and Cr resonances but exclude the 1.3 ppm lactate component and overlapping lipids. Surrounding RF(mix) and RF(rd) are magnetic field gradient pulses of equal magnitude but opposite signs to enable the rephasing of the zero-quantum lactate coherence and the creation of a stimulated echo for singlets within the pulse passbands. The sequence is designed to retain half the original lactate and singlet signal intensities. Theoretical predictions were confirmed experimentally at 1.5T using phantom acquisitions. The lipid suppression factor was measured to be over 10(3).

  View details for Web of Science ID 000172432900025

  View details for PubMedID 11746591

• Magnetic resonance imaging for the evaluation of hydronephrosis, reflux and renal scarring in children JOURNAL OF UROLOGY Rodriguez, L. V., Spielman, D., Herfkens, R. J., Shortliffe, L. D. 2001; 166 (3): 1023-1027

  Abstract

  We studied the effectiveness of magnetic resonance imaging (MRI) for evaluating hydronephrosis, differential renal function, vesicoureteral reflux and renal scarring in children.A total of 16 patients with hydronephrosis were evaluated with MRI. Coronal T1 and axial T1 and T2-weighted images were obtained before and after the administration of intravenous contrast material. Patients with vesicoureteral reflux underwent magnetic resonance voiding cystourethrography. Differential renal function was estimated from differential parenchymal volumes determined from MRI using computer software. The results were compared to standard imaging modalities.A total of 19 MRI studies were performed in 16 patients, including 3 for ureteropelvic junction obstruction, 11 for vesicoureteral reflux and 2 for other conditions. MRI provided the best anatomic detail and clear corticomedullary differentiation. MRI identified renal scarring and cortical thinning in 8 cases, while mercaptoacetyltriglycine 3 scans did not show any renal scarring and single photon emission computerized tomography-dimercapto-succinic acid nuclear scans diagnosed only 4 of 5 cases. There was good correlation between differential function obtained from nuclear scans and differential parenchymal volumes obtained from MRI (correlation coefficient 0.86, r2 = 0.74). Magnetic resonance voiding cystourethrography diagnosed reflux in 4 of 5 patients in whom vesicoureteral reflux was previously documented by standard voiding cystourethrography.MRI provides an alternative for the evaluation of hydronephrosis in children by combining the information provided by functional and anatomic nuclear scans, voiding cystourethrography and ultrasonography in a single study without ionizing radiation. MRI appears to be as good as existing modalities in the evaluation of renal scarring and cortical thinning.

  View details for Web of Science ID 000170453600083

  View details for PubMedID 11490289

• Effects of forced diving on the spleen and hepatic sinus in northern elephant seal pups PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Thornton, S. J., Speilman, D. M., Pelc, N. J., Block, W. F., Crocker, D. E., Costa, D. P., LeBoeuf, B. J., Hochachka, P. W. 2001; 98 (16): 9413-9418

  Abstract

  In phocid seals, an increase in hematocrit (Hct) accompanies diving and periods of apnea. The variability of phocid Hct suggests that the total red cell mass is not always in circulation, leading researchers to speculate on the means of blood volume partitioning. The histology and disproportionate size of the phocid spleen implicates it as the likely site for RBC storage. We used magnetic resonance imaging on Northern elephant seals to demonstrate a rapid contraction of the spleen and a simultaneous filling of the hepatic sinus during forced dives (P < 0.0001, R(2) = 0.97). The resulting images are clear evidence demonstrating a functional relationship between the spleen and hepatic sinus. The transfer of blood from the spleen to the sinus provides an explanation for the disparity between the timing of diving-induced splenic contraction ( approximately 1-3 min) and the occurrence of peak Hct (15-25 min). Facial immersion was accompanied by an immediate and profound splenic contraction, with no further significant decrease in splenic volume after min 2 (Tukey-Kramer HSD, P = 0.05). At the conclusion of the dive, the spleen had contracted to 16% of its predive volume (mean resting splenic volume = 3,141 ml +/- 68.01 ml; 3.54% of body mass). In the postdive period, the spleen required 18-22 min to achieve resting volume, indicating that this species may not have sufficient time to refill the spleen when routinely diving at sea, which is virtually continuous with interdive surface intervals between 1 and 3 min.

  View details for Web of Science ID 000170216900090

  View details for PubMedID 11481497

  View details for PubMedCentralID PMC55435

• 3 Tesla 1H-magnetic resonance spectroscopic (MRS) detection of cerebral gamma-aminobutyric acid (GABA) in bipolar disorder patients and healthy volunteers Wang, P. W., Sachs, N., Sailasuta, N., Adalsteinsson, E., Spielman, D., Ketter, T. A. ELSEVIER SCIENCE INC. 2001: 27S–27S

  View details for Web of Science ID 000168163000093

• Longitudinal decline of the neuronal marker NAA in Alzheimer's disease as measured by 1H magnetic resonance spectroscopic imaging Adalsteinsson, E., SULLIVAN, E. V., Keinhans, N., Spielman, D. M., Pfefferbaum, A. ELSEVIER SCIENCE INC. 2001: 332–32

  View details for Web of Science ID 000167154800024

• Optimal voxel size for measuring global gray and white matter proton metabolite concentrations using chemical shift imaging MAGNETIC RESONANCE IN MEDICINE Hanson, L. G., Adalsteinsson, E., Pfefferbaum, A., Spielman, D. M. 2000; 44 (1): 10-18

  Abstract

  Quantification of gray and white matter levels of spectroscopically visible metabolites can provide important insights into brain development and pathological conditions. Chemical shift imaging offers a gain in efficiency for estimation of global gray and white matter metabolite concentrations compared to single voxel methods. In the present study, the optimal voxel size is calculated from segmented human brain data and accompanying field maps. The optimal voxel size is found to be approximately 8 cc, but a wide range of values, 4-64 cc, can be chosen with little increase in estimated concentration error (<15%). Magn Reson Med 44:10-18, 2000.

  View details for Web of Science ID 000087917000003

  View details for PubMedID 10893515

• Longitudinal decline of the neuronal marker N-acetyl aspartate in Alzheimer's disease LANCET Adalsteinsson, E., SULLIVAN, E. V., Kleinhans, N., Spielman, D. M., Pfefferbaum, A. 2000; 355 (9216): 1696-1697

  Abstract

  In patients with Alzheimer's disease, but not in health controls, longitudinal magnetic resonance spectroscopy shows a striking decline in the neuronal marker, N-acetyl aspartate, despite little decline in underlying grey-matter volume.

  View details for Web of Science ID 000086983800017

  View details for PubMedID 10905250

• Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder BIOLOGICAL PSYCHIATRY Winsberg, M. E., Sachs, N., Tate, D. L., Adalsteinsson, E., Spielman, D., Ketter, T. A. 2000; 47 (6): 475-481

  Abstract

  N-acetyl aspartate (NAA) is an amino acid present in high concentrations in neurons and is thus a putative neuronal marker. In vivo proton magnetic resonance spectroscopy ((1)H MRS) studies have shown lower NAA concentrations in patients with various neurodegenerative disorders, suggesting decreased neuronal number, size, or function. Dorsolateral prefrontal (DLPF) NAA has not been extensively assessed in bipolar disorder patients, but it could be decreased in view of consistent reports of decreased DLPF cerebral blood flow and metabolism in mood disorders. We measured DLPF NAA in patients with bipolar disorder and healthy control subjects using in vivo (1)H MRS.We obtained ratios of NAA, choline, and myoinositol (mI) to creatine-phosphocreatine (Cr-PCr) in bilateral DLPF 8-mL voxels of 20 bipolar patients (10 Bipolar I, 10 Bipolar II) and 20 age- and gender-matched healthy control subjects using (1)H MRS.DLPF NAA/Cr-PCr ratios were lower on the right hemisphere (p<.03) and the left hemisphere (p<.003) in bipolar disorder patients compared with healthy control subjects.These preliminary data suggest that bipolar disorder patients have decreased DLPF NAA/Cr-PCr. This finding could represent decreased neuronal density or neuronal dysfunction in the DLPF region.

  View details for Web of Science ID 000085836200001

  View details for PubMedID 10715353

• Motion correction and lipid suppression for H-1 magnetic resonance spectroscopy Scientific Meeting of the International-Society-for-Magnetic-Resonance-in-Medicine Star-Lack, J. M., Adalsteinsson, E., Gold, G. E., Ikeda, D. M., Spielman, D. M. JOHN WILEY & SONS INC. 2000: 325–30

  Abstract

  Spectral/spatial spin-echo pulses with asymmetric excitation profiles were incorporated into a PRESS-based localization sequence to provide lipid suppression while retaining a sufficient amount of water to allow for correction of motion-induced shot-to-shot phase variations. 1H magnetic resonance spectroscopy data were acquired at 1.5 Tesla from a motion phantom and in vivo from the human liver, kidney, and breast. The results demonstrated that lipids in the chemical shift stopband were completely suppressed and that full metabolite signal intensity was maintained after implementation of a regularization algorithm based on phasing the residual water signal. Liver and kidney spectra contained a large resonance at 3.2 ppm that was ascribed to trimethylammonium moieties (betaine plus choline) and a weaker signal at 3.7 ppm that may result from glycogen. A breast spectrum from a histologically proven invasive ductal carcinoma displayed a highly elevated choline signal (3.2 ppm) relative to that from a normal volunteer.

  View details for Web of Science ID 000085559100001

  View details for PubMedID 10725872

• In vivo H-1 MR spectroscopy of human head and neck lymph node metastasis and comparison with oxygen tension measurements AMERICAN JOURNAL OF NEURORADIOLOGY Star-Lack, J. M., Adalsteinsson, E., Adam, M. F., Terris, D. J., Pinto, H. A., Brown, J. M., Spielman, D. M. 2000; 21 (1): 183-193

  Abstract

  Current diagnostic methods for head and neck metastasis are limited for monitoring recurrence and assessing oxygenation. 1H MR spectroscopy (1H MRS) provides a noninvasive means of determining the chemical composition of tissue and thus has a unique potential as a method for localizing and characterizing cancer. The purposes of this investigation were to measure 1H spectral intensities of total choline (Cho), creatine (Cr), and lactate (Lac) in vivo in human lymph node metastases of head and neck cancer for comparison with normal muscle tissue and to examine relationships between metabolite signal intensities and tissue oxygenation status.Volume-localized Lac-edited MRS at 1.5 T was performed in vivo on the lymph node metastases of 14 patients whose conditions were untreated and who had primary occurrences of squamous cell carcinoma. MRS measurements were acquired also from the neck muscle tissue of six healthy volunteers and a subset of the patients. Peak areas of Cho, Cr, and Lac were calculated. Tissue oxygenation (pO2) within the abnormal lymph nodes was measured independently using an Eppendorf polarographic oxygen electrode.Cho:Cr ratios were significantly higher in the nodes than in muscle tissue (node Cho:Cr = 2.9 +/- 1.6, muscle Cho:Cr = 0.55 +/- 0.21, P = .0006). Lac was significantly higher in cancer tissue than in muscle (P = .01) and, in the nodes, showed a moderately negative correlation with median pO2 (r = -.76) over a range of approximately 0 to 30 mm Hg. Nodes with oxygenation values less than 10 mm Hg had approximately twice the Lac signal intensity as did nodes with oxygenation values greater than 10 mm Hg (P = .01). Cho signal intensity was not well correlated with pO2 (r = -.46) but seemed to decrease at higher oxygenation levels (>20 mm Hg).1H MRS may be useful for differentiating metastatic head and neck cancer from normal muscular tissue and may allow for the possibility of assessing oxygenation. Potential clinical applications include the staging and monitoring of treatment.

  View details for PubMedID 10669248

• Reduced spatial side lobes in chemical-shift imaging MAGNETIC RESONANCE IN MEDICINE Adalsteinsson, E., Star-Lack, J., Meyer, C. H., Spielman, D. M. 1999; 42 (2): 314-323

  Abstract

  Density-weighted k-space sampling with spiral trajectories is used to reduce spatial side lobes in chemical-shift imaging (CSI). In this method, more time is spent collecting data at the center of k space and less time at the edges of k space in order to make the sampling density proportional to a given apodization function, subject to constraints imposed by gradient performance and Nyquist sampling. The efficient k-space coverage of spiral-based trajectories enables good control over the sampling density within practical in vivo scan times. The density-weighted acquisition is compared to a conventional, nonweighted spiral sampling without the application of a window function. For a fixed voxel size and imaging time, the noise variance is observed to be the same for both cases, while spatial side lobes are greatly reduced with the variable-density sampling. This method is demonstrated on a normal volunteer by imaging of brain metabolites at 1.5 T with both single slice CSI and volumetric CSI. Magn Reson Med 42:314-323, 1999.

  View details for Web of Science ID 000081758100014

  View details for PubMedID 10440957

• Differences in dorsolateral prefrontal cortex N-acetyl aspartate in bipolar disorder subtypes using 1H MRS Winsberg, M. E., Sachs, N., Tate, D. L., Spielman, D. M., Ketter, T. A. ELSEVIER SCIENCE INC. 1999: 125S–125S

  View details for Web of Science ID 000079911600404

• In vivo brain concentrations of N-acetyl compounds, creatine, and choline in Alzheimer disease ARCHIVES OF GENERAL PSYCHIATRY Pfefferbaum, A., Adalsteinsson, E., Spielman, D., SULLIVAN, E. V., Lim, K. O. 1999; 56 (2): 185-192

  Abstract

  Alzheimer disease (AD) and normal aging result in cortical gray matter volume deficits. The extent to which the remaining cortex is functionally compromised can be estimated in vivo with magnetic resonance spectroscopic imaging.To assess the effects of age and dementia on gray matter and white matter concentrations of 3 metabolites visible in the proton spectrum: N-acetyl compounds, present only in living neurons; creatine plus phosphocreatine, reflecting high-energy phosphate metabolism; and choline, increasing with membrane synthesis and degradation.Fifteen healthy young individuals, 19 healthy elderly individuals, and 16 patients with AD underwent 3-dimensional magnetic resonance spectroscopic imaging and memory and language testing.Gray matter N-acetyl compound concentrations (signal intensity corrected for the amount of brain tissue contributing to the magnetic resonance spectroscopic imaging signal) was significantly reduced only in patients with AD, even though both the AD and elderly control groups had substantial gray matter volume deficits relative to the young control group. Both the healthy elderly and AD groups had abnormally high gray matter creatine plus phosphocreatine concentrations. Gray matter choline concentrations were higher in the elderly than the younger controls, and even higher in the AD group than in the elderly control group. Functional significance of these findings was supported by correlations between poorer performance on recognition memory tests and lower gray matter N-acetyl compounds in elderly controls and higher gray matter creatine plus phosphocreatine and choline concentrations in patients with AD.Cortical gray matter volume deficits in patients with AD are accompanied by disease-related increases in gray matter choline concentrations suggestive of cellular degeneration and reduced N-acetyl compound concentrations, with possible effects on behavioral function.

  View details for Web of Science ID 000078553600010

  View details for PubMedID 10025444

• In vivo spectroscopic quantification of the N-acetyl moiety, creatine, and choline from large volumes of brain gray and white matter: Effects of normal aging MAGNETIC RESONANCE IN MEDICINE Pfefferbaum, A., Adalsteinsson, E., Spielman, D., SULLIVAN, E. V., Lim, K. O. 1999; 41 (2): 276-284

  Abstract

  Volumetric proton magnetic resonance spectroscopic imaging (MRSI) was used to generate brain metabolite maps in 15 young and 19 elderly adult volunteers. All subjects also had structural MR scans, and a model, which took into account the underlying structural composition of the brain contributing to each metabolite voxel, was developed and used to estimate the concentration of the N-acetyl-moiety (NAc), creatine (Cr), and choline (Cho) in gray matter and white matter. NAc concentration (signal intensity per unit volume of brain) was higher in gray than white matter and did not differ between young and old subjects despite significant gray matter volume deficits in the older subjects. To the extent that NAc is an index of neuronal integrity, the available gray matter appears to be intact in these older healthy adults. Cr concentrations were much higher in gray than white matter and significantly higher in the old than young subjects. Cho concentration in gray matter was also significantly higher in old than young subjects. Independent determination of metabolite values rather than use of ratios is essential for characterizing age-related changes in brain MRS metabolites.

  View details for Web of Science ID 000078804500010

  View details for PubMedID 10080274

• Spatially resolved two-dimensional spectroscopy MAGNETIC RESONANCE IN MEDICINE Adalsteinsson, E., Spielman, D. M. 1999; 41 (1): 8-12

  Abstract

  A method is presented to collect spatially resolved two-dimensional spectra on a conventional clinical scanner. Time-varying gradients during the readout period rapidly sample data simultaneously for two spatial and two spectral dimensions. The k-space trajectories are based on spiral paths that make efficient use of the gradient hardware. A gridding algorithm is used for reconstruction. With the spiral-based readout gradients, current single-voxel two-dimensional techniques can be extended to spatially resolved volumetric acquisitions. The method is demonstrated with a two-dimensional J-resolved acquisition of a phantom with separate compartments of lactic acid and ethyl alcohol in water. Data were acquired with a spatial resolution of 18 x 18 pixels over a 24 cm field of view, 400 Hz spectral bandwidth in the chemical shift dimension with a 3.8 Hz resolution, and 50 Hz spectral bandwidth in the second frequency dimension with a 1.56 Hz resolution.

  View details for Web of Science ID 000078336800003

  View details for PubMedID 10025605

• Feasibility study of lactate imaging of head and neck tumors NMR IN BIOMEDICINE Adalsteinsson, E., Spielman, D. M., Pauly, J. M., Terris, D. J., Sommer, G., Macovski, A. 1998; 11 (7): 360-369

  Abstract

  A proton spectroscopic imaging sequence was used to investigate the feasibility of lactate imaging in head and neck tumors. The sequence employs a two-shot lactate editing method with inversion recovery for additional lipid suppression, and a restricted field of view to suppress motion artifacts. Variations in acquisition parameters and two different receive coils were investigated on twelve patients. Elevated lactate was detected in three patients, no lactate was observed in seven patients, and two studies were inconclusive because of severe motion or inhomogeneity artifacts. Best results were obtained with an anterior/posterior neck coil at a 288 ms echo time (TE).

  View details for Web of Science ID 000077335700005

  View details for PubMedID 9859942

• Strategy for lipid suppression in lactate imaging using STIR-DQCT: A study of hypoxic-ischemic brain injury MAGNETIC RESONANCE IN MEDICINE Nakai, T., Rhine, W. D., Okada, T., Stevenson, D. K., Spielman, D. M. 1998; 40 (4): 629-632

  Abstract

  In vivo lactate detection using gradient enhanced double quantum coherence transfer (DQCT) was significantly improved by addition of short-time-inversion-recovery (STIR). Phantom studies demonstrated lipid suppression down to the background noise level with 33% loss of lactate signal. In vivo studies using a rabbit model of hypoxic and unilateral-ischemic brain injury showed reduction down to 29 +/- 11% in lipids with inversion times between 140 and 170 ms. Lactate signals on the ischemic side were 51 +/- 53% higher than the nonischemic side at the peak of hypoxia. STIR-DQCT can be a useful robust method of obtaining metabolic maps of lactate in vivo.

  View details for PubMedID 9771580

• Magnetic resonance imaging for the evaluation of hydronephrosis, reflux, and renal scarring in children. Rodriguez, L. V., Spielman, D., Herfkens, R. J., Shortliffe, L. M. AMER ACAD PEDIATRICS. 1998: 874–75

  View details for Web of Science ID 000075810500474

• Quantitative assessment of improved homogeneity using higher-order shims for spectroscopic imaging of the brain MAGNETIC RESONANCE IN MEDICINE Spielman, D. M., Adalsteinsson, E., Lim, K. O. 1998; 40 (3): 376-382

  Abstract

  Magnetic field homogeneity is of major concern for in vivo spectroscopy, and with the increased use of volumetric chemical shift imaging (CSI) techniques, the ability to shim over a large volume of tissue is now one of the primary limiting constraints in performing these studies. In vivo shimming is routinely performed using linear shim correction terms, and although many scanners are also equipped with additional resistive shim supplies that can provide second and third-order shim fields, they are often not used due to the additional effort and scan time required. The question as to how much improvement can be achieved using additional higher-order shims compared with the linear shims alone was quantitatively addressed. Performance measures for both intervoxel B0 uniformity and intravoxel T2* line broadening were evaluated for 15 normal volunteers. The analysis tools developed in this study, along with the summarized data, can be useful in deciding if a given application warrants the additional time, effort, and expense (if additional hardware needs to be purchased) of implementing higher-order shimming routines. For CSI studies of the brain, the use of the higher-order shims, compared with linear terms alone, yielded approximately 30% greater volume of brain tissue that could be shimmed within typical constraints for intervoxel B0 shifts and intravoxel T2* linebroadening. In addition, a regional analysis shows significant improvement in the homogeneity within specific areas of the brain, particularly those near the skull.

  View details for Web of Science ID 000075570500006

  View details for PubMedID 9727940

• In vivo lactate editing with simultaneous detection of choline, creatine, NAA, and lipid singlets at 1.5 T using PRESS excitation with applications to the study of brain and head and neck tumors JOURNAL OF MAGNETIC RESONANCE Star-Lack, J., Spielman, D., Adalsteinsson, E., Kurhanewicz, J., Terris, D. J., Vigneron, D. B. 1998; 133 (2): 243-254

  Abstract

  Two T2-independent J-difference lactate editing schemes for the PRESS magnetic resonance spectroscopy localization sequence are introduced. The techniques, which allow for simultaneous acquisition of the lactate doublet (1.3 ppm) and edited singlets upfield of and including choline (3.2 ppm), exploit the dependence of the in-phase intensity of the methyl doublet upon the time interval separating two inversion (BASING) pulses applied to its coupling partner after initial excitation. Editing method 1, which allows for echo times TE = n/J (n = 1, 2, 3, . . . . ), alters the BASING carrier frequency for each of two cycles so that, for one cycle, the quartet is inverted, whereas, for the other cycle, the quartet is unaffected. Method 2, which also provides water suppression, allows for editing for TE > 1/J by alternating, between cycles, the time interval separating the inversion pulses. Experimental results were obtained at 1.5 T using a Shinnar Le-Roux-designed maximum phase inversion pulse with a filter transition bandwidth of 55 Hz. Spectra were acquired from phantoms and in vivo from the human brain and neck. In a neck muscle study, the lipid suppression factor, achieved partly through the use of a novel phase regularization algorithm, was measured to be over 10(3). Spectra acquired from a primary brain and a metastatic neck tumor demonstrated the presence of lactate and choline signals consistent with abnormal spectral patterns. The advantages and limitations of the methods are analyzed theoretically and experimentally, and significance of the results is discussed.

  View details for Web of Science ID 000075748200001

  View details for PubMedID 9716465

• Volumetric spectroscopic imaging with spiral-based k-space trajectories MAGNETIC RESONANCE IN MEDICINE Adalsteinsson, E., Irarrazabal, P., Topp, S., Meyer, C., Macovski, A., Spielman, D. M. 1998; 39 (6): 889-898

  Abstract

  Spiral-based k-space trajectories were applied in a spectroscopic imaging sequence with time-varying readout gradients to collect volumetric chemical shift information. In addition to spectroscopic imaging of low signal-to-noise ratio (SNR) brain metabolites, the spiral trajectories were used to rapidly collect reference signals from the high SNR water signal to automatically phase the spectra and to aid the reconstruction of metabolite maps. Spectral-spatial pulses were used for excitation and water suppression. The pulses were designed to achieve stable phase profiles in the presence of up to 20% variation in the radiofrequency field. A gridding algorithm was used to resample the data onto a rectilinear grid before fast Fourier transforms. This method was demonstrated by in vivo imaging of brain metabolites at 1.5 T with 10 slices of 18 x 18 pixels each. Nominal voxel size was 1.1 cc, spectral bandwidth was 400 Hz, scan time was 18 min for the metabolite scan and 3 min for the reference scan.

  View details for Web of Science ID 000073759600006

  View details for PubMedID 9621912

• Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder Winsberg, M. E., Sachs, N., Tate, D. L., Dunai, M., Strong, C. M., Spielman, D. M., Ketter, T. A. ELSEVIER SCIENCE INC. 1998: 23S–23S

  View details for Web of Science ID 000073240700076

• Proton magnetic resonance spectroscopic imaging of cortical gray and white matter in schizophrenia 6th International Congress on Schizophrenia Research Lim, K. O., Adalsteinsson, E., Spielman, D., SULLIVAN, E. V., Rosenbloom, M. J., Pfefferbaum, A. AMER MEDICAL ASSOC. 1998: 346–52

  Abstract

  To apply in vivo proton magnetic resonance spectroscopy imaging estimates of N-acetylaspartate (NAA), a neuronal marker, to clarify the relative contribution of neuronal and glial changes to the widespread volume deficit of cortical gray matter seen in patients with schizophrenia with magnetic resonance images.Ten male veterans meeting criteria of the DSM-IV, for schizophrenia and 9 healthy age-matched men for comparison were scanned using spectroscopic, anatomical, and field-map sequences. Instrument and collection variables were standardized to allow an estimation of comparable values for NAA, choline, and creatine for all subjects. Metabolite values from each voxel on 3 upper cortical slices were regressed against the gray tissue proportion of that voxel to derive estimates of gray and white matter NAA, creatine, and choline concentrations.The volume of cortical gray matter was reduced in patients with schizophrenia, but NAA signal intensity from a comparable region was normal. In contrast, the volume of cortical white matter was normal in patients with schizophrenia, but NAA signal intensity from a comparable region was reduced.The lack of reduction in gray matter NAA signal intensity suggests that the cortical gray matter deficit in these patients involved both neuronal and glial compartments rather than a neurodegenerative process in which there is a decrease in the neuronal relative to the glial compartment. Reduced white matter NAA signal intensity without a white matter volume deficit may reflect abnormal axonal connections.

  View details for Web of Science ID 000072993300009

  View details for PubMedID 9554430

• Impaired cerebrovascular autoregulation after hypoxic-ischemic injury in extremely low-birth-weight neonates: Detection with power and pulsed wave Doppler US 82nd Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America Blankenberg, F. G., Loh, N. N., Norbash, A. M., Craychee, J. A., Spielman, D. M., Person, B. L., Berg, C. A., Enzmann, D. R. RADIOLOGICAL SOC NORTH AMER. 1997: 563–68

  Abstract

  To evaluate regional cerebral blood flow with power and pulsed wave Doppler ultrasound (US) in extremely low-birth-weight neonates with periventricular leukomalacia (PVL), germinal matrix hemorrhage (GMH), or both.The lenticulostriate arteries of 17 preterm neonates (birth weight < or = 1,100 g) were assessed daily with Doppler US during the first 5-6 days of life. The mean arterial pressure and bilateral peak velocity, resistive index, coronal vascular cross-sectional area, and product of the peak velocity and vascular cross-sectional area were measured.Five neonates developed PVL, GMH, or both; results of follow-up examinations in 11 patients were normal. One neonate with severe intrauterine growth retardation and renal tubular acidosis was excluded. Neonates with PVL, GMH, or both showed significantly greater mean values and more variable values of vascular cross-sectional area and product of peak velocity and cross-sectional area than neonates without PVL or GMH (P < .025). Mean resistive index was significantly lower in neonates with PVL, GMH, or both than in neonates without (P < .01). There were no significant differences between mean arterial pressure in neonates with and those without PVL, GMH, or both.By enabling the detection of autoregulatory fluctuations in cerebral blood flow associated with hypoxic-ischemic injury, power and pulsed wave Doppler US may enable identification of preterm neonates who are at risk of developing PVL, GMH, or both during the 1st week of life.

  View details for PubMedID 9356646

• Dynamic shimming for multi-slice magnetic resonance imaging MAGNETIC RESONANCE IN MEDICINE Morrell, G., Spielman, D. 1997; 38 (3): 477-483

  Abstract

  Dynamic shimming has been implemented in three pulse sequences on a commercial GE Signa 1.5-T imaging system. Multi-slice field maps are acquired before the imaging sequence, and linear shim terms and center frequencies are calculated for each slice. During the imaging scan, the linear shim terms and center frequency are set before each pulse sequence repetition according to the current slice. Acquisition of multi-slice field maps and calculation of shim terms and center frequency for each slice are accomplished in a matter of seconds. Pulse sequences require only minimal modification to add dynamic shimming capability. Results are shown for a fat saturation spin-echo sequence, a single-shot echo-planar gradient-recalled echo sequence, and a spiral acquisition gradient-recalled echo sequence. In all cases, dynamic shimming with shim currents and center frequency optimized for each slice is shown to give better results than constant shim currents and a single center frequency optimized for the entire volume of interest.

  View details for Web of Science ID A1997XW16200015

  View details for PubMedID 9339449

• Quantitative analysis of apoptotic cell death using proton nuclear magnetic resonance spectroscopy BLOOD Blankenberg, F. G., Katsikis, P. D., STORRS, R. W., Beaulieu, C., Spielman, D., Chen, J. Y., Naumovski, L., Tait, J. F. 1997; 89 (10): 3778-3786

  Abstract

  Quantification of apoptotic cell death in vivo has become an important area of investigation in patients with acute lymphoblastic leukemia (ALL). We have devised a noninvasive analytical method to estimate the percentage of apoptotic lymphoblasts in doxorubicin-treated Jurkat T-cell ALL cultures, using proton nuclear magnetic resonance spectroscopy (1H NMR). We have found that the ratio of the methylene (CH2) resonance (at 1.3 ppm) to the methyl (CH3) resonance (at 0.9 ppm) signal intensity, as observed by 1H NMR, is directly proportional to the percentage of apoptotic lymphoblasts in vitro. The correlation between the CH2/CH3 signal intensity ratio and the percentage of apoptotic lymphoblasts was optimal 24 to 28 hours after doxorubicin treatment (r2 = .947, N = 27 samples). There was also a direct temporal relationship between an increase in the CH2/CH3 signal intensity ratio and the onset of apoptosis as detected by nuclear morphologic analysis, fluorescein-annexin V flow cytometry, and DNA gel electrophoresis. Thin-layer chromatography confirmed that a dynamic and/or compositional change of the plasma membrane, rather than increases in lipase activity or fatty acid production, appears to account for the increase in the CH2/CH3 signal intensity ratio during apoptosis. 1H NMR may have clinical utility for the early noninvasive assessment of chemotherapeutic efficacy in patients with ALL.

  View details for PubMedID 9160684

• Proton spectroscopy reveals normal NAA concentration in cortical gray matter in schizophrenic patients Lim, K. O., Adalsteinsson, E., Spielman, D., SULLIVAN, E. V., Pfefferbaum, A. ELSEVIER SCIENCE BV. 1997: 179–80

  View details for Web of Science ID A1997WP19600509

• Estimating NAA in cortical gray matter with applications for measuring changes due to aging 3rd Annual Meeting of the Society-of-Magnetic-Resonance Lim, K. O., Spielman, D. M. WILLIAMS & WILKINS. 1997: 372–77

  Abstract

  N-acetylaspartic acid (NAA), a prominent peak in the proton spectrum, is an amino acid thought to be present almost exclusively in neurons and their dendritic and axonal extensions. While 1H MRS studies are showing promise in identifying NAA deficits in different patient groups, unwanted lipid signal from subcutaneous fat surrounding the skull, and necessarily large voxels have limited investigators' ability to assess NAA in cortical gray matter. Here we report a technique developed to derive estimates of NAA signal from cortical gray matter. This approach uses an inversion recovery imaging pulse sequence with a long TE to suppress lipid signal from the scalp and information from concurrently obtained structural MR images to determine the CSF, white and gray matter composition of each spectroscopic voxel. A regression analysis is then used to estimate what NAA levels would be in "pure" white and gray matter voxels. This technique has been applied to demonstrate reduced NAA gray/white levels in the brains of five healthy older compared with five healthy younger women.

  View details for Web of Science ID A1997WJ66400010

  View details for PubMedID 9055227

• Proton magnetic resonance spectroscopy of a gray matter heterotopia NEUROLOGY Marsh, L., Lim, K. O., SULLIVAN, E. V., Lane, B., Spielman, D. 1996; 47 (6): 1571-1574

  Abstract

  We used proton magnetic resonance spectroscopy to examine resonances representing metabolites containing N-acetyl (NA) groups (predominantly N-acetyl aspartate), choline, and creatine within a large left-hemispheric gray matter heterotopia (GMH) in a 35-year-old man with corpus callosum agenesis. In contrast to normal brain tissue, including gray matter regions, heterotopic gray matter was characterized by relatively increased choline and creatine resonances and a normal NA signal. These data suggest increased cellular activity or persistent immature neuronal tissue in GMH relative to unaffected tissue.

  View details for Web of Science ID A1996VX50700040

  View details for PubMedID 8960748

• A model for detecting early metabolic changes in neonatal asphyxia by 1H-MRS JOURNAL OF MAGNETIC RESONANCE IMAGING Nakai, T., Rhine, W. D., Enzmann, D. R., Stevenson, D. K., Spielman, D. M. 1996; 6 (3): 445-452

  Abstract

  In newborn rabbits, the early cerebral metabolic changes caused by hypoxic-ischemic (H-I) insult was examined by using volume localized 1H-MRS (STEAM). Partial ischemia was caused by unilateral carotid artery ligation, and hypoxia was induced by 10% oxygen inspiration for 150 minutes. Lactate immediately increased after hypoxia induction and almost disappeared 120 to 150 minutes after removal of hypoxia in both H-I and hypoxia-only experiments. Lactate production correlated well with decrease of the blood oxygen saturation. More lactate was produced on ischemic side 50 minutes post-hypoxia induction in H-I study. Ischemia alone did not cause any significant lactate production. Lactate caused by hypoxia can be dynamically monitored by localized 1H-MRS. Existence of regional ischemia can induce greater anaerobic glycolysis and may affect the pattern of brain injury under hypoxia. 1H-MRS is a sensitive tool to detect the acute metabolic change caused by H-I insult.

  View details for Web of Science ID A1996UM58400004

  View details for PubMedID 8724409

• Magnetic resonance imaging of human brain function SURGICAL NEUROLOGY Moseley, M. E., deCrespigny, A., Spielman, D. M. 1996; 45 (4): 385-390

  Abstract

  Previously the exclusive domain of the technology of positron emission tomography, functional MRI is now proving capable of mapping functional regions of the human cortex in near real time during specific task activations or in response to any hemodynamic stress. Of particular interest is the opportunity to observe secondary cortical responses, activation due to imagined tasks, memory function, time-resolved pathways through cortical regions, and activation in sub-cortical structures.One method of functional MRI uses blood oxygenation changes, which can be imaged continuously while functional centers are being stimulated. Image intensity can become darker if there is more deoxygenated blood and brighter if more oxygenated blood enters the brain. This concepts works in all perfused tissues in the body, and allows use of the blood oxygenation mechanism to image neuronal activation. A second method takes advantage of the fact that the protons within the MRI slice are always partially saturated by the rapid rate of imaging. As blood flow delivers unsaturated blood water protons into an imaged slice, these arterially-delivered protons will appear very bright in the image. Visualization of this effect is accomplished by simple image subtraction or by comparison of intensity changes as a function of the paradigm application frequency. Using either approach leads directly to a functional map.At present, clinical applications are rapidly moving toward routine non-invasive mapping of distortions of the functional motor and somatosensory cortex and other cortical regions as a result of brain tumors. Other clinical applications include the observation of the effect of degenerative diseases such as multiple sclerosis. Alzheimer's disease, stroke, migraine, epilepsy, and other diseases causing neuronal loss and Parkinsonism. Functional MRI and its applications will continue to grow exponentially throughout the decade.

  View details for Web of Science ID A1996UE70600031

  View details for PubMedID 8607092

• Detection of apoptotic cell death by proton nuclear magnetic resonance spectroscopy BLOOD Blankenberg, F. G., STORRS, R. W., Naumovski, L., Goralski, T., Spielman, D. 1996; 87 (5): 1951-1956

  Abstract

  Cells undergoing apoptosis (programmed cell death) display profound morphologic and biochemical changes in the nucleus, cytoplasm, and plasma membrane. We have shown a direct temporal relationship between the onset of apoptosis in Jurkat T-cell lymphoblast cultures and a greater than two-fold increase in the signal intensity of the methylene resonance (at 1.3 ppm) as observed by proton nuclear magnetic resonance spectroscopy (1H NMR). The increase in the methylene resonance intensity was seen when apoptosis was induced by serum deprivation, glucocorticoid, and doxorubicin treatment but not in necrotic (nonapoptotic) cell death. We have found similar changes in a variety of other cell lines undergoing apoptosis including the Hut 78 T-cell leukemia, JY natural killer T-cell leukemia, Daudi B-cell lymphoma, HeLa, and 3T3 fibroblast cell lines. Furthermore, this spectral change was diminished in Bcl-2 overexpressing HL-60 cell cultures treated with doxorubicin, which were relatively resistant to apoptosis, as compared to apoptotic HL-60 cultures. 1H NMR spectroscopy therefore may be useful in detecting apoptotic cell death in vivo.

  View details for Web of Science ID A1996TY33900034

  View details for PubMedID 8634443

• MELAS: Clinical and pathologic correlations with MRI, xenon/CT, and MR spectroscopy NEUROLOGY Clark, J. M., Marks, M. P., Adalsteinsson, E., Spielman, D. M., Shuster, D., Horoupian, D., Albers, G. W. 1996; 46 (1): 223-227

  Abstract

  We describe the clinical, imaging, and pathologic findings in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). The patient experienced her first stroke-like episode at age forty-four. Brain MRI, obtained at symptom onset, at 3 weeks, and at 1 year, revealed migrating T2-weighted hyperintensities in the temporal/parietal and occipital cortices and later revealed atrophy. Abnormal cerebrovascular reserve was evident on xenon/CT four days after the first MRI. MR spectroscopy at 1 year revealed increased lactate in both the occipital and temporal lobes. Histologic sections demonstrated spongy degeneration of the cortex that was most prominent at the crests of the gyri. Electron microscopy of the blood vessels showed increased numbers of abnormal mitochondria within the vascular smooth muscle and in endothelial cells. We hypothesize that the stroke-like episodes in MELAS may be due to impaired autoregulation secondary to the impaired metabolic activity of mitochondria in the endothelial and smooth muscle cells of blood vessels.

  View details for Web of Science ID A1996TR67100045

  View details for PubMedID 8559380

• Clinical aspects of DWI NMR IN BIOMEDICINE Moseley, M. E., Butts, K., Yenari, M. A., Marks, M., deCrespigny, A. 1995; 8 (7-8): 387-396

  Abstract

  Diffusion-weighted MR imaging (DWI) is capable of imaging ischemia-induced changes in water protons in either animal or man. Technical developments are described that allow the routine clinical utility of DWI in a stroke setting to provide objective criteria beyond the neurological exam by which the pathophysiology of stroke can be evaluated. To date, DWI has provided unique information concerning detection and evaluation of acute, symptomatic lesions from older, chronic strokes, detection and localization of small deep infarcts and reversible ischemic neurologic deficits and transient ischemia. Clinical DWI studies suggest that the temporal behaviour of ADC can critically improve the evaluation of clinical ischemia.

  View details for Web of Science ID A1995UL58700011

  View details for PubMedID 8739275

• SPIRAL IMAGING ON A SMALL-BORE SYSTEM AT 4.7T MAGNETIC RESONANCE IN MEDICINE Spielman, D. M., Pauly, J. M. 1995; 34 (4): 580-585

  Abstract

  Spiral imaging has a number of advantages for ultrafast data acquisition. However, implementation on high-field small-bore systems requires carefully addressing the issues of inhomogeneity-induced blurring and gradient hardware constraints. In this paper, spiral imaging on a 40-cm-bore 4.7T CSI Omega System (Bruker Instruments) is discussed. A constant-voltage gradient waveform design algorithm is developed to reduce readout times as well as minimize waveform distortions due to gradient amplifier nonlinearities. Residual errors are then measured and taken into account in the image reconstruction procedure. Multiple spiral interleaves as well as a multifrequency reconstruction algorithm are used to decrease blurring of off-resonance spins. Both phantom and in vivo images demonstrate the performance of the resulting pulse sequences.

  View details for Web of Science ID A1995RX75100013

  View details for PubMedID 8524026

• MAGNETIC-RESONANCE FLUOROSCOPY USING SPIRALS WITH VARIABLE SAMPLING DENSITIES MAGNETIC RESONANCE IN MEDICINE Spielman, D. M., Pauly, J. M., Meyer, C. H. 1995; 34 (3): 388-394

  Abstract

  The imaging of dynamic processes in the body is of considerable interest in interventional examinations as well as kinematic studies, and spiral imaging is a fast magnetic resonance imaging technique ideally suited for such fluoroscopic applications. In this manuscript, magnetic resonance fluoroscopy pulse sequences in which interleaved spirals are used to continuously acquire data and reconstruct one movie frame for each repetition time interval are implemented. For many applications, not all of k-space needs to be updated each frame, and nonuniform k-space sampling can be used to exploit this rapid imaging strategy by allowing variable update rates for different spatial frequencies. Using the appropriate reconstruction algorithm, the temporal updating rate for each spatial frequency is effectively proportional to the corresponding k-space sampling density. Results from a motion phantom as well as in in vivo gadolinium diethylenetriaminopentaacetic acid (Gd-DTPA) bolus tracking studies in a rat model demonstrate the high temporal resolution achievable using these techniques as well as the tradeoffs available with nonuniform sampling densities. This paper focuses on the acquisition of real-time dynamic information, and all images presented are reconstructed retrospectively. The issues of real-time data reconstruction and display are not addressed.

  View details for Web of Science ID A1995RR68700015

  View details for PubMedID 7500878

• 3-DIMENSIONAL SPECTROSCOPIC IMAGING WITH TIME-VARYING GRADIENTS MAGNETIC RESONANCE IN MEDICINE Adalsteinsson, E., Irarrazabal, P., Spielman, D. M., Macovski, A. 1995; 33 (4): 461-466

  Abstract

  A spectroscopic imaging sequence with a time-varying readout gradient in the slice selection direction is used to image multiple contiguous slices. For a given voxel size, the imaging time and signal-to-noise ratio of the three-dimensional spectroscopic sequence are the same as for a single slice acquisition without the oscillating readout gradient. The data reconstruction employs a gridding algorithm in two dimensions to interpolate the nonuniformly sampled data onto a Cartesian grid, and a fast Fourier transform in four dimensions: three spatial dimensions and the spectral dimension. The method is demonstrated by in vivo imaging of NAA in human brain at 1.5 T with 10 slices of 16 x 16 pixels spectroscopic images acquired in a total scan time of 17 min.

  View details for Web of Science ID A1995QP45500001

  View details for PubMedID 7776875

• ULTRAFAST CONTRAST-ENHANCED MAGNETIC-RESONANCE-IMAGING OF CONGENITAL HYDRONEPHROSIS IN A RAT MODEL Annual Meeting of the Section on Urology of the American-Academy-of-Pediatrics Fichtner, J., Spielman, D., Herfkens, R., BOINEAU, F. G., Lewy, J. E., Shortliffe, L. M. WILLIAMS & WILKINS. 1994: 682–87

  Abstract

  Since new ultrafast magnetic resonance imaging (MRI) might offer unique advantages for evaluating renal blood flow, anatomy and urinary excretion, we used this technique to characterize a rat model with congenital partial ureteropelvic junction obstruction. MRI of 9 rats from an inbred colony with unilateral congenital (nonsurgical) hydronephrosis was compared with the contralateral nonhydronephrotic kidney serving as control. Our new imaging technique consisted of a 1-minute ultrafast gradient recalled imaging sequence during the first minute (64 images per imaging time 960 milliseconds) after contrast bolus injection with gadolinium-diethylenetriaminepentaacetic acid for assessment of renal blood flow followed by a 30-minute period with image acquisition every 30 seconds to study contrast distribution and excretion. Signal intensities were analyzed continuously over selected, different regions of interest. Anatomic analysis of MRI noncontrast studies showed precise delineation of the hydronephrotic pelvis and corticomedullary junction. After contrast gadolinium-diethylenetriaminepentaacetic acid injection signal intensity from the region of interest from hydronephrotic kidneys differed from nonhydronephrotic kidneys by showing less cortical decrease, suggesting decreased blood flow, less medullary decrease and delayed contrast excretion. Clear contrast distribution among the cortex, medulla and collecting system allowed selective estimation of different regions of interest and excellent anatomic evaluation. Renal anatomy and renal pelvic pressures were confirmed after scans were completed. Ultrafast contrast enhanced MRI allows simultaneous assessment of renal morphology, blood flow and function. In hydronephrotic partially obstructed kidneys distinct flow and excretion patterns measured with contrast enhanced MRI allow differentiation between the obstructed and nonobstructed kidney on physiological rather than purely anatomic means. This imaging technique may provide a useful method of evaluating congenital hydronephrosis obviating the need for multiple different diagnostic procedures.

  View details for Web of Science ID A1994NW33000024

  View details for PubMedID 8021995

• MAGNETIC-RESONANCE SPECTROSCOPIC IMAGING OF ETHANOL IN THE HUMAN BRAIN - A FEASIBILITY STUDY ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Spielman, D. M., Glover, G. H., Macovski, A., Pfefferbaum, A. 1993; 17 (5): 1072-1077

  Abstract

  The in vivo distribution of ethanol in normal human brain following the consumption of a moderate amount of alcohol was measured using magnetic resonance spectroscopic imaging. Three subjects were studied, and the spatial distribution of brain ethanol, 60-min postingestion and measured at a spatial resolution of 1.5 cm, was found to be highly nonuniform with the relative ethanol signal in cerebral spinal fluid, gray matter, and white matter determined to be 1.00, 0.72, and 0.37, respectively. These spectroscopic imaging results indicate that whereas in vivo magnetic resonance studies of ethanol are feasible, quantitative studies of alcohol need to account carefully for the various tissue types within the observed volume.

  View details for Web of Science ID A1993ME46800024

  View details for PubMedID 8279668

• INCORPORATING LACTATE LIPID DISCRIMINATION INTO A SPECTROSCOPIC IMAGING SEQUENCE MAGNETIC RESONANCE IN MEDICINE Adalsteinsson, E., Spielman, D. M., Wright, G. A., Pauly, J. M., Meyer, C. H., Macovski, A. 1993; 30 (1): 124-130

  Abstract

  A spectroscopic imaging sequence incorporating a two-shot lactate editing method was used in two human brain studies to image lactate and NAA. The subtractive editing method allows separate images of lactate, NAA, and lipids to be collected during a single study with no SNR penalty. The sequence uses a spectral-spatial excitation for slice selection and water suppression, and employs inversion recovery and an echo time of 136 ms for additional lipid suppression.

  View details for Web of Science ID A1993LK91600018

  View details for PubMedID 8371666

• ECHO-PLANAR SPIN-ECHO AND INVERSION PULSES MAGNETIC RESONANCE IN MEDICINE Pauly, J., Spielman, D., Macovski, A. 1993; 29 (6): 776-782

  Abstract

  The echo-planar k-space trajectory can be used as the basis for any two-dimensional selective pulse. The main application is spectral-spatial pulses, which must be based on the echo-planar trajectory. In this paper we show how echo-planar spin-echo (EPSE) pulses may be designed.

  View details for Web of Science ID A1993LF39300008

  View details for PubMedID 8350720

• LIPID-SUPPRESSED SINGLE-SECTION AND MULTISECTION PROTON SPECTROSCOPIC IMAGING OF THE HUMAN BRAIN JOURNAL OF MAGNETIC RESONANCE IMAGING Spielman, D. M., Pauly, J. M., Macovski, A., Glover, G. H., Enzmann, D. R. 1992; 2 (3): 253-262

  Abstract

  Spectroscopic images of the brain have great potential in disease diagnosis and treatment monitoring. Unfortunately, interfering lipid signals from subcutaneous fat and poor water suppression due to magnetic field inhomogeneities can make such images difficult to obtain. A pulse sequence that uses inversion recovery for lipid suppression and a spectral-spatial refocusing pulse for water suppression is introduced. In contrast to methods that eliminate fat signal by restricting the excited volume to lie completely within the brain, inversion-recovery techniques allow imaging of an entire section without such restrictions. In addition, the spectral-spatial pulse was designed to provide water suppression insensitive to a reasonable range of B0 and B1 inhomogeneities. Several data processing algorithms have also been developed and used in conjunction with the new pulse sequence to produce metabolite maps covering large volumes of the human brain. Images from single- and multisection studies demonstrate the performance of these techniques.

  View details for Web of Science ID A1992HV08100001

  View details for PubMedID 1627859

• INHOMOGENEITY CORRECTION FOR INVIVO SPECTROSCOPY BY HIGH-RESOLUTION WATER REFERENCING MAGNETIC RESONANCE IN MEDICINE Webb, P., Spielman, D., Macovski, A. 1992; 23 (1): 1-11

  Abstract

  One of the most common sources of distortion in in vivo spectroscopy is the inhomogeneity of the main magnetic field. This effect is particularly problematic when performing spectroscopic imaging, as the shim cannot be simultaneously optimized for all voxels. In this paper we present a technique to measure inhomogeneity rapidly, then show how to use the measurement to improve the analysis of the spectrum. This technique can be applied in conjunction with any spectroscopic localization method and any spectral quantitation algorithm. We present results from spectroscopic imaging of phantoms, then show application to a single-voxel water-suppressed proton brain study. We find that the quantitation of the in vivo spectrum is made immune to inhomogeneous line broadening.

  View details for Web of Science ID A1992HA59900001

  View details for PubMedID 1734171

• SPECTROSCOPIC IMAGING WITH MULTIDIMENSIONAL PULSES FOR EXCITATION - SIMPLE MAGNETIC RESONANCE IN MEDICINE Spielman, D., Pauly, J., Macovski, A., ENZMANN, D. 1991; 19 (1): 67-84

  Abstract

  Proton spectroscopy and spectroscopic imaging in the human brain require the elimination of both water and lipid signals. Strong lipid signals from subcutaneous fat are usually eliminated by confining the excited volume to lie wholly within the skull. Water suppression, however, can be difficult due to both B0 and RF inhomogeneities, which are particularly troublesome in imaging experiments where a relatively large region-of-interest (ROI) is typical. In this paper, we discuss the use of multidimensional selective-excitation pulses (e.g., pulses that are simultaneously selective along two axes) to both define the ROI and provide the necessary water suppression. Pulse sequences providing three-dimensional localization along with water suppression that is insensitive to a range of B0 and RF inhomogeneities are described. Spectra and spectroscopic images (voxel volume = 3.4 cc. acquisition time = 38 min) of various 1H metabolites from a patient with an astrocytoma show clear differences between normal and cancerous tissues and demonstrate the ability of these techniques to be used in vivo.

  View details for Web of Science ID A1991FJ08400006

  View details for PubMedID 2046539

• H-1 SPECTROSCOPIC IMAGING USING A SPECTRAL SPATIAL EXCITATION PULSE MAGNETIC RESONANCE IN MEDICINE Spielman, D., Meyer, C., Macovski, A., ENZMANN, D. 1991; 18 (2): 269-279

  Abstract

  Excellent water suppression is required to perform in vivo 1H spectroscopic experiments. However water suppression is difficult due to both B0 and RF inhomogeneities. These inhomogeneities are particularly troublesome in spectroscopic imaging experiments where water suppression is required throughout some large region of interest. In this paper, we propose the use of spectral-spatial excitation pulses for such experiments. These two-dimensional pulses are shown to provide water suppression that is insensitive to a range of B0 and RF variations while simultaneously providing spatial localization. Experimental results including images (with voxel volumes ranging from 3.4 to 1.5 cc) of various brain metabolites from both a normal volunteer and a patient with a metastatic lung carcinoma are presented.

  View details for Web of Science ID A1991FF36100002

  View details for PubMedID 2046512

• A FAST SPECTROSCOPIC IMAGING METHOD USING A BLIPPED PHASE ENCODE GRADIENT MAGNETIC RESONANCE IN MEDICINE Webb, P., Spielman, D., Macovski, A. 1989; 12 (3): 306-315

  Abstract

  Many methods of chemical shift imaging have been described recently. In most cases, these methods couple resolution and imaging time. The most flexible methods use time-varying gradients to cover a large region of k space on each excitation. We present here a new time-varying gradient method that offers a decrease in scan time (when SNR is sufficient), simplifies the reconstruction problem by retaining an essentially rectilinear sampling grid, and makes efficient use of scan time by minimizing gradient reversals. Implementation on a standard high-field imaging system (GE Signa) is discussed, and experimental results are shown. An application of the method to the generation of water reference data sets is described.

  View details for Web of Science ID A1989CD30300002

  View details for PubMedID 2628681

• WATER REFERENCING FOR SPECTROSCOPIC IMAGING MAGNETIC RESONANCE IN MEDICINE Spielman, D., Webb, P., Macovski, A. 1989; 12 (1): 38-49

  Abstract

  A water referencing algorithm for addressing the spectroscopic imaging problems of low SNR and main field inhomogeneities is proposed. Using the location of the water peak from each voxel and additional a priori information results in a parametric estimation problem. Optimum estimates of the desired metabolite concentration can then be computed and displayed in an image format. The algorithm is shown to be very stable in the presence of noise and is insensitive to Bo inhomogeneity. A detailed error analysis as well as extensions to the basic data model are also discussed. Results from both 1H and 31P experiments are presented to verify the predicted good performance even with extremely low signal-to-noise ratio data.

  View details for Web of Science ID A1989AT67000004

  View details for PubMedID 2607959

• A STATISTICAL FRAMEWORK FOR INVIVO SPECTROSCOPIC IMAGING JOURNAL OF MAGNETIC RESONANCE Spielman, D., Webb, P., Macovski, A. 1988; 79 (1): 66-77

  View details for Web of Science ID A1988P794900007

• EIGENSTRUCTURE APPROACH TO DIRECTIONS-OF-ARRIVAL ESTIMATION IN IR DETECTOR ARRAYS APPLIED OPTICS Spielman, D., Paulraj, A., KAILATH, T. 1987; 26 (2): 199-202

  View details for Web of Science ID A1987F775000010

  View details for PubMedID 20454104

• INVIVO SPECTROSCOPIC MAGNETIC-RESONANCE-IMAGING USING ESTIMATION THEORY MAGNETIC RESONANCE IN MEDICINE Macovski, A., Spielman, D. 1986; 3 (1): 97-104

  Abstract

  The ability to map spectroscopic components for in vivo application is a highly desirable goal. Thusfar it has been unavailable because of the low SNR inherent in the measurement of each voxel. In this paper we deal with this low SNR in two ways. First, estimation theory, using a priori data, is used to estimate the amplitudes in each voxel. Second, the resultant estimates are presented in an image format so that they are readily correlated with anatomical and physiological patterns. A computer simulation is presented of a case where the SNR is -10 dB. At this level, conventional Fourier transform spectroscopy provides meaningless results. Using estimation theory and an imaging format, a simulated lesion is readily seen.

  View details for Web of Science ID A1986A105500011

  View details for PubMedID 3959894