Quantitative MRI of Cerebral Arterial Blood Volume

Baseline cerebral arterial blood volume (CBVa) and its change are important for potential diagnosis of vascular dysfunctions, the determination of functional reactivity, and the interpretation of BOLD fMRI. To quantitative measure baseline CBVa non-invasively, we developed arterial spin labeling methods with magnetization transfer (MT) or bipolar gradients by utilizing differential MT or diffusion properties of tissue vs. arteries. Cortical CBVa of isoflurane-anesthetized rats was 0.6 – 1.4 ml/100 g. During 15-s forepaw stimulation, CBVa change was dominant, while venous blood volume change was minimal. This indicates that the venous CBV increase may be ignored for BOLD quantification for a stimulation duration of less than 15 s. By incorporating BOLD fMRI with varied MT effects in a cat visual cortical layer model, the highest ΔCBVa was observed at layer 4, while the highest BOLD signal was detected at the surface of the cortex, indicating that CBVa change is highly specific to neural activity. The CBVa MRI techniques provide quantified maps, thus, may be valuable tools for routine determination of vessel viability and function, as well as the identification of vascular dysfunction

Perfusion MR imaging: Evolution from initial development to functional studies

A critical indicator of tissue viability and function is blood delivery to the capillary bed (referred to as perfusion or tissue/capillary blood flow), so the measurement of this process has been pursued by many MR scientists. Perfusion MRI is currently an effective tool to non-invasively quantify cerebral blood flow (CBF) and to easily obtain its relative change due to neural activity or other stimulus. This article describes the author's experiences in perfusion MRI over the past quarter-century, including initial development of the field, development of a flow-sensitive alternating inversion recovery (FAIR) MRI technique, development of a functional oxygen consumption MRI measurement approach, validation of the FAIR technique, characterization of perfusion changes induced by neural activity, and determination of arterial blood volume

Evolution of the dynamic changes in functional cerebral oxidative metabolism from tissue mitochondria to blood oxygen

The dynamic properties of the cerebral metabolic rate of oxygen consumption (CMR O2 ) during changes in brain activity remain unclear. Therefore, the spatial and temporal evolution of functional increases in CMR O2 was investigated in the rat somato-sensory cortex during forelimb stimulation under a suppressed blood flow response condition. Temporally, stimulation elicited a fast increase in tissue mitochondria CMR O2 described by a time constant of B1 second measured using flavoprotein autofluorescence imaging. CMR O2 -driven changes in the tissue oxygen tension measured using an oxygen electrode and blood oxygenation measured using optical imaging of intrinsic signal followed; however, these changes were slow with time constants of B5 and B10 seconds, respectively. This slow change in CMR O2 -driven blood oxygenation partly explains the commonly observed post-stimulus blood oxygen level-dependent (BOLD) undershoot. Spatially, the changes in mitochondria CMR O2 were similar to the changes in blood oxygenation. Finally, the increases in CMR O2 were well correlated with the evoked multi-unit spiking activity. These findings show that dynamic CMR O2 calculations made using only blood oxygenation data (e.g., BOLD functional magnetic resonance imaging (fMRI)) do not directly reflect the temporal changes in the tissue's mitochondria metabolic rate; however, the findings presented can bridge the gap between the changes in cellular oxidative rate and blood oxygenation

Magnetic resonance imaging of the Amine-Proton EXchange (APEX) dependent contrast

Chemical exchange between water and labile protons from amino-acids, proteins and other molecules can be exploited to provide tissue contrast with magnetic resonance imaging (MRI) techniques. Using an offresonance Spin-Locking (SL) scheme for signal preparation is advantageous because the image contrast can be tuned to specific exchange rates by adjusting SL pulse parameters. While the amide-proton transfer (APT) contrast is obtained optimally with steady-state preparation, using a low power and long irradiation pulse, image contrast from the faster amine-water proton exchange (APEX) is optimized in the transient state with a higher power and a shorter SL pulse. Our phantom experiments show that the APEX contrast is sensitive to protein and amino acid concentration, as well as pH. In vivo 9.4-T SL MRI data of rat brains with irradiation parameters optimized to slow exchange rates have a sharp peak at 3.5 ppm and also broad peak at − 2 to − 5 ppm, inducing negative contrast in APT-weighted images, while the APEX image has large positive signal resulting from a weighted summation of many different amine-groups. Brain ischemia induced by cardiac arrest decreases pure APT signal from~1.7% to~0%, and increases the APEX signal from~8% to~16%. In the middle cerebral artery occlusion (MCAO) model, the APEX signal shows different spatial and temporal patterns with large inter-animal variations compared to APT and water diffusion maps. Because of the similarity between the chemical exchange saturation transfer (CEST) and SL techniques, APEX contrast can also be obtained by a CEST approach using similar irradiation parameters. APEX may provide useful information for many diseases involving a change in levels of proteins, peptides, amino-acids, or pH, and may serve as a sensitive neuroimaging biomarker

Layer-specific fMRI responses to excitatory and inhibitory neuronal activities in the olfactory bulb

High-resolution functional magnetic resonance imaging (fMRI) detects localized neuronal activity via the hemodynamic response, but it is unclear whether it accurately identifies neuronal activity specific to individual layers. To address this issue, we preferentially evoked neuronal activity in superficial, middle, and deep layers of the rat olfactory bulb: the glomerular layer by odor (5% amyl acetate), the external plexiform layer by electrical stimulation of the lateral olfactory tract (LOT), and the granule cell layer by electrical stimulation of the anterior commissure (AC), respectively. Electrophysiology, laser-Doppler flowmetry of cerebral blood flow (CBF), and blood oxygenation level-dependent (BOLD) and cerebral blood volume-weighted (CBV) fMRI at 9.4 T were performed independently. We found that excitation of inhibitory granule cells by stimulating LOT and AC decreased the spontaneous multi-unit activities of excitatory mitral cells and subsequently increased CBF, CBV, and BOLD signals. Odor stimulation also increased the hemodynamic responses. Furthermore, the greatest CBV fMRI responses were discretely separated into the same layers as the evoked neuronal activities for all three stimuli, whereas BOLD was poorly localized with some exception to the poststimulus undershoot. In addition, the temporal dynamics of the fMRI responses varied depending on the stimulation pathway, even within the same layer. These results indicate that the vasculature is regulated within individual layers and CBV fMRI has a higher fidelity to the evoked neuronal activity compared with BOLD. Our findings are significant for understanding the neuronal origin and spatial specificity of hemodynamic responses, especially for the interpretation of laminar-resolution fMRI. © 2015 the authors115151sciescopu

Bucillamine prevents cisplatin-induced ototoxicity through induction of glutathione and antioxidant genes.

Bucillamine is used for the treatment of rheumatoid arthritis. This study investigated the protective effects of bucillamine against cisplatin-induced damage in auditory cells, the organ of Corti from postnatal rats (P2) and adult Balb/C mice. Cisplatin increases the catalytic activity of caspase-3 and caspase-8 proteases and the production of free radicals, which were significantly suppressed by pretreatment with bucillamine. Bucillamine induces the intranuclear translocation of Nrf2 and thereby increases the expression of γ-glutamylcysteine synthetase (γ-GCS) and glutathione synthetase (GSS), which further induces intracellular antioxidant glutathione (GSH), heme oxygenase 1 (HO-1) and superoxide dismutase 2 (SOD2). However, knockdown studies of HO-1 and SOD2 suggest that the protective effect of bucillamine against cisplatin is independent of the enzymatic activity of HO-1 and SOD. Furthermore, pretreatment with bucillamine protects sensory hair cells on organ of Corti explants from cisplatin-induced cytotoxicity concomitantly with inhibition of caspase-3 activation. The auditory-brainstem-evoked response of cisplatin-injected mice shows marked increases in hearing threshold shifts, which was markedly suppressed by pretreatment with bucillamine in vivo. Taken together, bucillamine protects sensory hair cells from cisplatin through a scavenging effect on itself, as well as the induction of intracellular GSH

Light-chain amyloidosis presenting with rapidly progressive submucosal hemorrhage of the stomach

SummaryThe gastrointestinal tract is frequently in involved light-chain (AL) amyloidosis, but significant hemorrhagic complications are rare. A 71-year-old man presented to our hospital with dyspepsia and heartburn for 1 month. Gastroscopy revealed a large submucosal hematoma at the gastric fundus. Two days later, a follow-up gastroscopy indicated extensive expansion of the hematoma throughout the upper half of the stomach. The hematoma displayed ongoing expansion during the endoscopic examination, suggesting that rupture was imminent. Emergency total gastrectomy was performed, and amyloidosis was confirmed after examining the surgical specimen. Bone marrow examination revealed multiple myeloma, and serum immunoglobulin assay confirmed the diagnosis of myeloma-associated AL amyloidosis. At manuscript submission, the patient was doing well and was undergoing chemotherapy