Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine

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MRI initially and, 10 years later, functional magnetic resonance imaging fMRI have become major modalities for research and diagnostic medicine, as well as for animal physiology studies, since the mids. The growth internationally has been from a few low-field magnets in the United States, Scotland, and England in the mids to 40, installations worldwide in The field of NMR spectroscopy being pursued by chemists and physicists for research in molecular structure and dynamics has followed a parallel path of development, but with higher fields and much smaller samples Figure 4.

The initial medical applications used horizontal bore electromagnets with a field strength of 0. In the s commercialization was successful for superconducting systems at 0. In the mids General Electric marketed worldwide superconducting whole body systems for clinical medicine at 1. Safety and health effects studies commenced in the late s and continue to the present time while keeping pace with new methods of acquisition of the magnetic resonance signals and the increases in magnetic field strength Appendix F.

Each major increase in field has also introduced new technical challenges and problems that have required creative scientific and engineering solutions in order to realize the potential to improve image quality.

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The evolution of higher field systems has continued. By success in development of a whole body 4 T system was reported Barfuss et al.

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The upper group is magnets for analytical NMR applications. The step curve is the FDA guideline that does not denote a hazard threshold but only caution. Rooney, G. Johnson, X. Li, E. Cohen, S. Kim, K. Ugurbil, and C. Springer, , The magnetic field and tissue dependences of human brain 1H2O longitudinal relaxation in vivo, Magnetic Resonance in Medicine However, ultimately the main industrial effort focused on developing scanners operating at 3 T, and these systems are replacing 1.

Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine

Much of the early 3 T developments emphasized brain imaging, partly motivated by the discovery of the benefits of blood oxygenation level-dependent susceptibility contrast as a measure of brain activity. This phenomenon is also known as fMRI. A compendium on ultrahigh-field magnetic resonance imaging was edited by Robitaille in Thus the major imaging equipment manufacturers, General Electric, Siemens, and Philips, along with vendors of research magnetic resonance e.

As already mentioned, there are approximately 50 human scanners operating at 7 T in the world today. An example of the demonstrable improvement in image quality over the past 30 years is shown in Figure 4. By two human imaging systems at 9. Smaller scanners operating at higher fields are in extensive use in animal research. Systems with warm bores of 21 and 40 cm operating at The One can conclude that This chronology is graphed in Figure 4. While magnet manufacture technology was progressing, in parallel there had to be improvements in shimming techniques and hardware.

These include radiofrequency RF transmission and reception coils; gradient coils and power supplies; spectrometer design and performance; and the associated pulse sequences needed. Sostman, D. Spencer, J. Gore, S. Spencer, W. Holcomb, P. Williamson, J. Prichard, C. Camputaro, R. Greenspan, and R. These advances have been and continue to be significant, with major new developments reported regularly.

In the recent past, for example, parallel imaging using large numbers of receiver coils has emerged as an important improvement for imaging, providing new ways to reduce imaging times and increase signal to noise; at the same time, parallel transmission methods are also demonstrating how some limitations of RF fields at high frequencies can be overcome.

Another notable innovation that arises only at very high fields when RF wavelengths are shortened is the use of traveling waves in MRI e. This development suggests that a new class of experimental techniques may be developed, introducing some of the concepts of image formation from coherent optics such as holographic imaging and interferometry.

These applications may develop significant importance as ultrahigh-field magnets and improvements in coil design arise.

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Currently, it has a range of wide-bore magnets at its Tallahassee and Gainesville facilities that are capable of performing MR using a variety of probes and scanners. Other wide-bore magnets at NHMFL have sufficient homogeneity for exposures of animals in order to explore unforeseen physiological effects at static fields beyond 20 T. The motivation for higher field imaging systems is to increase the signal-to-noise ratio SNR available for imaging, because the net nuclear magnetization induced in tissues scales linearly with the field, while the induced electromagnetic force emf in receiver coils also scales linearly with the frequency.

Increased SNR leads to increased sensitivity for detecting changes within tissues, improved spatial resolution imaging with smaller voxels , or shortening of data acquisition times. The main driver for development has been proton MRI, which largely depicts variations between tissues in proton mainly water hydrogen nuclei density and NMR relaxation times and provides exquisite anatomical images. In addition, there has been continual interest in the use of localized in vivo high-resolution NMR spectroscopy to study tissue metabolism and biochemistry. Proton magnetic resonance spectroscopy operates at the same frequency as proton MRI, but in addition there have been long-standing interest in and development of localized spectra from naturally occurring phosphorus compounds e.

Next, the committee highlights the many opportunities for medical science advances using much higher fields than are currently available. Note that many of the anticipated problems for proton studies at 20 T disappear for the other nuclei listed, as they have lower gyromagnetic ratios, hence lower NMR frequencies.

Physics of NMR for low gamma nuclei shows the time to acquire equivalent SNR data at 20 T will be reduced by a factor of 8 from that at 7 T and of 33 from that at 3 T, and spectral dispersion and relaxation time changes will allow investigations of metabolites in vivo that cannot be observed by any other method. As shown in Table 4. Moreover, not shown are the abundances in tissues of these nuclei, so it is important to adjust our expectations for applications based on knowledge of the local concentration of nuclei of interest.

For example, sodium concentration within cells is 10 M and in extracellular fluid is m M ,. This information, plus an assumption that the SNR is proportional to field strength, gyromagnetic ratio, and the square root of time, allows us to calculate the time and resolution obtainable. Although hyperpolarized compounds offer significant improvements in detection, there are clear needs to improve the sensitivity for detecting 13 C-labeled substrates limited to their Boltzmann magnetization. New insights into neurochemistry have emerged from the ability to study the metabolism of labeled compounds such as glucose and the kinetics of major brain neurotransmitters such as glutamate and GABA, while the synthesis and metabolism of other compounds such as glutamine and choline are of compelling importance in understanding the behaviors of many tumors.

Measurements of glycogen production and use are of great interest in metabolic studies of the brain, muscle, and liver. However, at its natural abundance, measurements of glycogen levels are possible but currently take too long and are poorly resolved. The gyromagnetic ratio is 7. The 17 O nucleus possesses a quadrupolar moment that can interact with local electric field gradients.

In addition, relaxation times are field independent, so that 17 O sensitivity gain with higher magnetic fields will enable imaging the dynamics of H 17 O in vivo at 9. This is a new method for noninvasive measurement of cerebral metabolism of oxygen. The importance of clinical studies of the local concentrations of sodium and potassium is a compelling reason for making available wide-bore magnets with field strengths significantly greater than available currently.

Detecting and measuring this gradient in vivo have been an unattainable goal of importance not only to fundamental biology but also to clinical issues such as mental disorders; tumor biology and response to therapy; heart failure; and diseases of the lungs and kidneys. Theoretically, sodium and potassium can be imaged in human subjects Parrish et al.

Using multiple quantum NMR techniques, it has been shown that the concentrations of intracellular sodium and extracellular sodium can be evaluated during normal and pathologic function e. It is possible to discriminate cation resonances using the difference in longitudinal relaxation values, which if sufficiently different in intracellular and extracellular environments allow simple inversion recovery pulse sequences e.

The most recent Twenty years ago the concept of 23 Na relaxographic imaging was introduced to intracellular sodium imaging without the use of spectral shift reagents, most of which are toxic Labadie et al. More recently, separation of signals representing intracellular and extracellular sodium has been demonstrated using longitudinal relaxometry on in vitro samples at 9.

An important potential clinical application is the investigation of migraine headaches, which affect 30 million U. This has important implications for therapy in renal disease and the management of hypertension Kopp, , a condition that affects 30 percent of U. Although sodium imaging at 3 T has been used to investigate these phenomena, higher fields would allow better resolution, shorter imaging times, and, most importantly, the ability to measure levels of the other relevant ions, chlorine and potassium.

The promise of imaging sodium, potassium, and chlorine such that, in principle, estimates can be made of the resting membrane potentials of the brain and heart in health and disease depends on the availability of fields approaching 20 T. Though the frequency of 31 P at 20 T will present penetration and homogeneity problems greater than other spins, these problems are well understood from experience with 1 H at 7 T MHz.

The promise for high-field chemical exchange saturation transfer 31 P CEST is that it could resolve all adenosine triphosphate ATP , adenosine diphosphate ADP , and adenosine monophosphate AMP signals and thus become an efficient, noninvasive diagnostic tool in heart disease. Selected Horizons for Proton Studies at 20 T. Although radio-frequency penetration for studying proton relaxation differences and chemical shift spectroscopy currently experiences engineering design difficulties up to the highest human magnet fields of In animals including nonhuman primates, cortical anatomic imaging at 7 T and 9.

Figure 4. The peaks of several of the compounds, such as glutamate Glu and glutamine Gln , are just resolved at 9. Gruetter, S. Weisdorf, V. Rajanayagan, M. Terpstra, et al. There would be considerable value to being able to routinely image cortex with resolutions times smaller—for example, to visualize cortical columns and cortical layers.

Detailed anatomy, fMRI, and spectroscopic studies such as shown for lower fields in Figure 4. One major important clinical goal would be to better understand dementia. Spectroscopic studies of the surface of the human heart for studies of congestive heart failure will most likely emphasize 13 C and 31 P. The gains in sensitivity for the lower gamma spins discussed above are substantially greater than will be experienced by the University of Minnesota when, as planned, it doubles the field of its human imaging magnet to The dispersion increase can enable metabolic studies heretofore not possible.

During the past 20 years a method of mapping imaging the metabolic activity of the brain in response to activation uses signal changes associated with changes. Development of high-field MRI, such as 7 T, is now the high-end research platform in neurosciences with the goal of studying the fundamental computational units that reside in submillimeter organizations Ugurbil, Imaging these units and their connectivity employs functional MRI that provides regional information on the neuronal activity changes in the brain.

The feasibility of this goal at 7 T was demonstrated by imaging noninvasively the ocular dominance columns Yacoub et al. However, magnetic fields much higher than 7 T are needed to achieve the SNR and data acquisition times required to decipher the neural code at the scale of fundamental computations.

Though functional MRI uses proton frequencies of MHz, penetration to depths of 3 cm in the human skull is not expected to be a problem at 20 T. Studies of RF safety for cell phone frequencies which are 2 to 3 times higher show the RF field can penetrate through bone and tissues to and beyond the cortex. In addition, fMRI is an approach that requires minimal power deposition and should be feasible even at 20 T.

The main technical challenges of performing fMRI at high magnetic field strengths have been solved for 7 T, and currently the whole brain can be imaged in subsecond intervals Moeller et al. Potential future applications using new rapid acquisition techniques include whole-brain connectivity analysis, including the dynamics of brain networks as recently demonstrated Smith et al. One of the most important applications of 20 T is in the use of CEST, as it will allow detection of exchangeable -NH protons or -OH protons within cells and, for example, the imaging of liver glycogen Sherry and Woods, Combined proton and 13 C studies of lipid and amino acid metabolism in vivo in human subjects relative to nutrition, obesity, and diabetes is another area enabled by high-field studies of muscle and adipose tissue of the limbs.

Imaging the distribution of safe stable-isotope-based compounds at very high fields will open new horizons in the applications of contrast-enhanced MRI. The advances in MRI clinical applications have been enabled partly by advances in the. When these agents are in the intravascular blood pool, they allow visualization of the vascular tree analogous to X-ray angiography, because the presence of the agent reduces the T1 relaxation of water protons in the blood. If a tissue region has increased permeability such that more contrast agent accumulates in that region e.

This allows identification of different tissue pathologies by MRI imaging methods used to bring out signals related to the relative decrease in T1. The barrier to improving sensitivity of the injected compounds is the inability to effectively restrict fast local motions of contrast agents attached to slow-tumbling scaffolds. Synthesis of new agents to reach the maximum sensitivity is theoretically attainable at 20 T because the slow-tumbling requirement does not apply. For T2 and fluorine agents, sensitivity can be increased by at least an order of magnitude compared to current experience at clinical field strengths of 3 T.

This translates to being able to image targets at subnanomolar concentrations e. Metals other than gadolinium become competitive in terms of sensitivity at 20 T because their fast electronic relaxation times no longer represent a limitation. Consequently, completely new classes of contrast agents become possible. In addition, the increased Curie spin of paramagnetic ions may allow for new ways of engineering more sensitive contrast agents. The implication is that although R2 decreases monotonically as field strength increases to 3 T as does R1 , consistent with the theory of a gradual fall in effectiveness of inter- and intramolecular dipole-dipole couplings that promote relaxation, some other mechanism s lead to an increase in R2.

The primary candidate for this relaxation is chemical exchange between labile protons notably -OH and -NH, -NH 2 and bulk water, which occurs at rates that depend on molecular structure, pH, and other factors and for which a quadratic field dependence may be predicted. Thus, Figure 4.

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The underlying molecular properties that give rise to this contrast may be sensitive to a completely different set of influences than those known at lower fields. The transition to contrast that reflects chemical exchange is of particular relevance. Zhong, J. Gore, and I. Armitage, , Contributions of chemical exchange and other relaxation mechanisms in protein solutions and tissues, Magnetic Resonance in Medicine 11 3 Copyright Wiley-Liss, Inc. The manifestation of this mechanism will be at high magnetic fields. Enhanced Contrast from Susceptibility Differences.

Suppose two adjacent tissues have slightly different susceptibilities. This will result in a change in homogeneity that will increase linearly with field:. The phase difference can lead to image distortions and voids due to phase cancellation effects. The effects noted at 4 T and 7 T will be greater by factors of more than 2 at 20 T. However, the distortion can be viewed as an effective contrast enhancement. This concept is already used at lower fields in susceptibility-weighted imaging, a technique that modulates the MRI signal intensity by local phase shifts to enhance vascular and other features.

Moreover, tissue layers or domains having dimensions of tens of microns and small susceptibility differences from adjacent tissues might be visualized at higher fields than currently available. Animal experiments at very high fields can evaluate the extent of the benefits as well as problems of susceptibility differences between adjacent tissues because large differences in susceptibility can exist between paramagnetic tissues e. The anisotropic magnetic susceptibility of neural tissues has already led to the development of imaging methods of the susceptibility tensor, from which new methods for mapping neural connectivity are emerging.

Susceptibility anisotropy within macromolecules and assemblages of molecules is discussed in Appendix F. Some of the potential benefits are related to the image contrast that results from bulk magnetic susceptibility differences in adjacent tissues due to compounds such as ferritin and myelin, both of which are found throughout brain tissue. In addition, the relative directional orientation of bundles of nerve fibers relative to the B 0 field will give an associated frequency shift that translates to image contrast, as shown in Figure 4.

In a , the specimen is orientated with fiber tracks parallel to the B 0 field and in b , the tracks are oriented both parallel and orthogonal to the B 0 field. The resolution is 0. Lee, K. Shmueli, M. Fukunaga, P.

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Merkle, A. Silva, and J. Duyn, , Sensitivity of MRI resonance frequency to the orientation of brain tissue microstructure, Proceedings of the National Academy of Sciences 11 Copyright National Academy of Sciences, U. As mentioned above, at very high fields when RF wavelengths are shortened traveling waves e. There will continue to be complications from the nonuniform distributions of relevant electromagnetic properties of tissues, but these may also open up opportunities for mapping such properties as new forms of tissue contrast.

For example, measuring the nonuniform distributions of RF fields at 7 T has provided preliminary images of distributions of tissue conductivity and permittivity, and at higher fields these variations should be more easily distinguished. Traveling wave methods may be adapted for such acquisitions, and the fact that image data can be detected at a distance from the object provides a compelling reason to continue to develop these methods at higher fields.

Because of the well-known frequency vs. The emf generated by moving conductors in the magnet oppose the voltage of the gradient power amplifier. This phenomenon will be more problematic at 20 T than experienced at 7 T even though nuclei of lower gyromagnetic ratios than those of protons are being studied because the effect is dependent on field and gradient strength rather than NMR frequency.

As magnetic resonance uses radio-frequency fields to excite nuclei, there are consequences from the interactions of the RF fields and the dielectric and resistive properties of the body e. These effects alter the B 1 transmitted field and spatially modulate the sensitivity of coils in reception, leading to spatial inhomogeneities Kangarlu et al. At RFs of MHz, the effective. These can result in serious imaging artifacts. Cognitive tasks where fMRS has been used and the major findings of the research are summarized below. From Wikipedia, the free encyclopedia.

Functional magnetic resonance spectroscopy of the brain Medical diagnostics Purpose uses magnetic resonance imaging to study brain metabolism Functional magnetic resonance spectroscopy of the brain fMRS uses magnetic resonance imaging MRI to study brain metabolism during brain activation.

Magnetic Resonance in Medicine. Quarterly Reviews of Biophysics. European Neuropsychopharmacology. Journal of Cerebral Blood Flow and Metabolism. Bibcode : PNAS The American Journal of Psychiatry. Topics in Magnetic Resonance Imaging. American Journal of Physiology. Endocrinology and Metabolism. Journal of Neurochemistry. Learning Disability Quarterly. A functional 1 H-MRS study". The Journal of Headache and Pain.

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Skip to Main Content. Shulman Douglas L. First published: 29 March About this book This book is unique in linking in vivo 13 C NMR measurements of neuronal activity and energetics with applications to functional imaging and certain disease states It provides a fundamental neurochemical explanation of brain activity applicable to functional imaging, theories of neuronal activity and disease states, e.

Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine
Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine
Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine
Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine
Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine
Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine
Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine Brain Energetics and Neuronal Activity: Applications to fMRI and Medicine

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