Functional magnetic resonance imaging (MRI) in the nonhuman primate promises to provide a much desired link between brain research in humans and the large body of systems neuroscience work in ...animals. We present here a novel high field, large-bore,
vertical MR system (7 T/60 cm, 300 MHz), which was optimized for neuroscientific research in macaque monkeys. A strong magnetic field was applied to increase sensitivity and spatial resolution for both MRI and spectroscopy. Anatomical imaging with voxel sizes as small as 75×150×300 μm
3 and with high contrast-to-noise ratios permitted the visualization of the characteristic lamination of some neocortical areas, e.g., Baillarger lines. Relaxation times were determined for different structures: at 7 T, T1 was 2.01/1.84/1.54 s in GM/GM-V1/WM, T2 was 59.1/54.4 ms in GM/WM and T2* was 29 ms. At 4.7 T, T1 was 25% shorter, T2 and T2* 18% longer compared to 7T. Spatiotemporally resolved blood-oxygen-level-dependent (BOLD) signal changes yielded robust activations and deactivations (negative BOLD), with average amplitudes of 4.1% and −2.4%, respectively. Finally, the first high-resolution (500 μm in-plane) images of cerebral blood flow in the anesthetized monkey are presented. On functional activation we observed flow increases of up to 38% (59 to 81 ml/100 g/min) in the primary visual cortex, V1. Compared to BOLD maps, functional CBF maps were found to be localized entirely within the gray matter, providing unequivocal evidence for high spatial specificity. The exquisite sensitivity of the system and the increased specificity of the hemodynamic signals promise further insights into the relationship of the latter to the underlying physiological activity.
The six cortical layers have distinct anatomical and physiological properties, like different energy use and different feedforward and feedback connectivity. It is not known if and how layer-specific ...neural processes are reflected in the fMRI signal. To address this question we used high-resolution fMRI to measure BOLD, CBV, and CBF responses to stimuli that elicit positive and negative BOLD signals in macaque primary visual cortex. We found that regions with positive BOLD responses had parallel increases in CBV and CBF, whereas areas with negative BOLD responses showed a decrease in CBF but an increase in CBV. For positive BOLD responses, CBF and CBV increased in the center of the cortex, but for negative BOLD responses, CBF decreased superficially while CBV increased in the center. Our findings suggest different mechanisms for neurovascular coupling for BOLD increases and decreases, as well as laminar differences in neurovascular coupling.
► High-resolution fMRI allows visualization of laminar differences in BOLD, CBV, and CBF ► CBF is decreased for negative BOLD while CBV is increased ► Positive and negative BOLD signals have different neurovascular coupling mechanisms ► Neurovascular coupling differs depending on cortical depth
Goense et al. use high-resolution fMRI to show that positive and negative BOLD responses have different neurovascular coupling mechanisms and that neurovascular coupling is cortical layer dependent. This potentially allows disentangling of feedforward, feedback, excitatory, or inhibitory processes using fMRI.
A hemispheric asymmetry in the functional activation of the human motor cortex during contralateral (C) and ipsilateral (I) finger movements, especially in right-handed subjects, was documented with ...nuclear magnetic resonance imaging at high field strength (4 tesla). Whereas the right motor cortex was activated mostly during contralateral finger movements in both right-handed (C/I mean area of activation = 36.8) and left-handed (C/I = 29.9) subjects, the left motor cortex was activated substantially during ipsilateral movements in left-handed subjects (C/I = 5.4) and even more so in right-handed subjects (C/I = 1.3).
Previous authors have shown that the transverse relaxivity R2* and frequency shifts that characterize gradient echo signal decay in magnetic resonance imaging are closely associated with the ...distribution of iron and myelin in the brain's white matter. In multiple sclerosis, iron accumulation in brain tissue may reflect a multiplicity of pathological processes. Hence, iron may have the unique potential to serve as an in vivo magnetic resonance imaging tracer of disease pathology. To investigate the ability of iron in tracking multiple sclerosis-induced pathology by magnetic resonance imaging, we performed qualitative histopathological analysis of white matter lesions and normal-appearing white matter regions with variable appearance on gradient echo magnetic resonance imaging at 7 Tesla. The samples used for this study derive from two patients with multiple sclerosis and one non-multiple sclerosis donor. Magnetic resonance images were acquired using a whole body 7 Tesla magnetic resonance imaging scanner equipped with a 24-channel receive-only array designed for tissue imaging. A 3D multi-gradient echo sequence was obtained and quantitative R2* and phase maps were reconstructed. Immunohistochemical stainings for myelin and oligodendrocytes, microglia and macrophages, ferritin and ferritin light polypeptide were performed on 3- to 5-µm thick paraffin sections. Iron was detected with Perl's staining and 3,3′-diaminobenzidine-tetrahydrochloride enhanced Turnbull blue staining. In multiple sclerosis tissue, iron presence invariably matched with an increase in R2*. Conversely, R2* increase was not always associated with the presence of iron on histochemical staining. We interpret this finding as the effect of embedding, sectioning and staining procedures. These processes likely affected the histopathological analysis results but not the magnetic resonance imaging that was obtained before tissue manipulations. Several cellular sources of iron were identified. These sources included oligodendrocytes in normal-appearing white matter and activated macrophages/microglia at the edges of white matter lesions. Additionally, in white matter lesions, iron precipitation in aggregates typical of microbleeds was shown by the Perl's staining. Our combined imaging and pathological study shows that multi-gradient echo magnetic resonance imaging is a sensitive technique for the identification of iron in the brain tissue of patients with multiple sclerosis. However, magnetic resonance imaging-identified iron does not necessarily reflect pathology and may also be seen in apparently normal tissue. Iron identification by multi-gradient echo magnetic resonance imaging in diseased tissues can shed light on the pathological processes when coupled with topographical information and patient disease history.
Magnetic resonance imaging (MRI) sensitivity approaches vessel specificity. We developed a single-vessel functional MRI (fMRI) method to image the contribution of vascular components to blood ...oxygenation level-dependent (BOLD) and cerebral blood volume (CBV) fMRI signal. We mapped individual vessels penetrating the rat somatosensory cortex with 100-ms temporal resolution by MRI with sensory or optogenetic stimulation. The BOLD signal originated primarily from venules, and the CBV signal from arterioles. The single-vessel fMRI method and its combination with optogenetics provide a platform for mapping the hemodynamic signal through the neurovascular network with specificity at the level of individual arterioles and venules.
Real-time visualization of metabolic processes in vivo provides crucial insights into conditions like cancer and metabolic disorders. Metabolic magnetic resonance imaging (MRI), by amplifying the ...signal of pyruvate molecules through hyperpolarization, enables non-invasive monitoring of metabolic fluxes, aiding in understanding disease progression and treatment response. Signal Amplification By Reversible Exchange (SABRE) presents a simpler, cost-effective alternative to dissolution dynamic nuclear polarization, eliminating the need for expensive equipment and complex procedures. We present the first in vivo demonstration of metabolic sensing in a human pancreatic cancer xenograft model compared to healthy mice. A novel perfluorinated Iridium SABRE catalyst in a fluorinated solvent and methanol blend facilitated this breakthrough with a 2.2-fold increase in 1-13Cpyruvate SABRE hyperpolarization. The perfluorinated moiety allowed easy separation of the heavy-metal-containing catalyst from the hyperpolarized 1-13Cpyruvate target. The perfluorinated catalyst exhibited recyclability, maintaining SABRE-SHEATH activity through subsequent hyperpolarization cycles with minimal activity loss after the initial two cycles. Remarkably, the catalyst retained activity for at least 10 cycles, with a 3.3-fold decrease in hyperpolarization potency. This proof-of-concept study encourages wider adoption of SABRE hyperpolarized 1-13Cpyruvate MR for studying in vivo metabolism, aiding in diagnosing stages and monitoring treatment responses in cancer and other diseases.
Hyperpolarized (HP) carbon-13 13C enables the specific investigation of dynamic metabolic and physiologic processes via in vivo MRI-based molecular imaging. As the leading HP metabolic agent, ...1-13Cpyruvate plays a pivotal role due to its rapid tissue uptake and central role in cellular energetics. Dissolution dynamic nuclear polarization (d-DNP) is considered the gold standard method for the production of HP metabolic probes; however, development of a faster, less expensive technique could accelerate the translation of metabolic imaging via HP MRI to routine clinical use. Signal Amplification by Reversible Exchange in SHield Enabled Alignment Transfer (SABRE-SHEATH) achieves rapid hyperpolarization by using parahydrogen (p-H2) as the source of nuclear spin order. Currently, SABRE is clinically limited due to the toxicity of the iridium catalyst, which is crucial to the SABRE process. To mitigate Ir contamination, we introduce a novel iteration of the SABRE catalyst, incorporating bis(polyfluoroalkylated) imidazolium salts. This novel perfluorinated SABRE catalyst retained polarization properties while exhibiting an enhanced hydrophobicity. This modification allows the easy removal of the perfluorinated SABRE catalyst from HP 1-13C-pyruvate after polarization in an aqueous solution, using the ReD-SABRE protocol. The residual Ir content after removal was measured via ICP-MS at 177 ppb, which is the lowest reported to date for pyruvate and is sufficiently safe for use in clinical investigations. Further improvement is anticipated once automated processes for delivery and recovery are initiated. SABRE-SHEATH using the perfluorinated SABRE catalyst can become an attractive low-cost alternative to d-DNP to prepare biocompatible HP 1-13C-pyruvate formulations for in vivo applications in next-generation molecular imaging modalities.Hyperpolarized (HP) carbon-13 13C enables the specific investigation of dynamic metabolic and physiologic processes via in vivo MRI-based molecular imaging. As the leading HP metabolic agent, 1-13Cpyruvate plays a pivotal role due to its rapid tissue uptake and central role in cellular energetics. Dissolution dynamic nuclear polarization (d-DNP) is considered the gold standard method for the production of HP metabolic probes; however, development of a faster, less expensive technique could accelerate the translation of metabolic imaging via HP MRI to routine clinical use. Signal Amplification by Reversible Exchange in SHield Enabled Alignment Transfer (SABRE-SHEATH) achieves rapid hyperpolarization by using parahydrogen (p-H2) as the source of nuclear spin order. Currently, SABRE is clinically limited due to the toxicity of the iridium catalyst, which is crucial to the SABRE process. To mitigate Ir contamination, we introduce a novel iteration of the SABRE catalyst, incorporating bis(polyfluoroalkylated) imidazolium salts. This novel perfluorinated SABRE catalyst retained polarization properties while exhibiting an enhanced hydrophobicity. This modification allows the easy removal of the perfluorinated SABRE catalyst from HP 1-13C-pyruvate after polarization in an aqueous solution, using the ReD-SABRE protocol. The residual Ir content after removal was measured via ICP-MS at 177 ppb, which is the lowest reported to date for pyruvate and is sufficiently safe for use in clinical investigations. Further improvement is anticipated once automated processes for delivery and recovery are initiated. SABRE-SHEATH using the perfluorinated SABRE catalyst can become an attractive low-cost alternative to d-DNP to prepare biocompatible HP 1-13C-pyruvate formulations for in vivo applications in next-generation molecular imaging modalities.
To elucidate the mechanism of magnetic resonance (MR) imaging contrast in multiple sclerosis (MS) lesion appearance by using susceptibility-weighted imaging and to assess with histologic correlation ...the role of iron and myelin in generating this MR imaging contrast.
Each patient provided written consent to a human subject protocol approved by an institutional review board. High-spatial-resolution susceptibility-weighted 7.0-T MR images were obtained in 21 patients with MS. Contrast patterns in quantitative phase and R2* images, derived from 7.0-T data, were investigated in 220 areas defined as chronic MS lesions on conventional T2-weighted fluid-attenuated inversion recovery, T2-weighted, and T1-weighted spin-echo images. The presence of positive or negative phase shifts (ie, decreased or increased MR frequency, respectively) was assessed in each lesion. In addition, postmortem MR imaging was performed at 7.0 T and 11.7 T, and its results were correlated with those of immunohistochemical staining specific for myelin, iron, and ferritin.
The majority (133 60.5% of 220) of the identified lesions had a normal phase and reduced R2*. A substantial fraction of the lesions (84 38.2% of 220) had negative phase shift, either uniformly or at their rim, and a variety of appearances on R2* maps. These two lesion contrast patterns were reproduced in the postmortem MR imaging study. Comparison with histologic findings showed that, while R2* reduction corresponded to severe loss of both iron and myelin, negative phase shift corresponded to focal iron deposits with myelin loss.
Combined analysis of 7.0-T R2* and phase data may help in characterizing the pathologic features of MS lesions. The observed R2* decreases suggest profound myelin loss, whereas negative phase shifts suggest a focal iron accumulation.
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