Acute toxicity of a nuclear magnetic resonance cerebral blood flow indicator in cats

We studied trifluoromethane as a potential gaseous indicator in nuclear magnetic resonance measurements of cerebral blood flow. We considered the effects of trifluoromethane on cerebral blood flow in 17 cats and on the electroencephalogram and electrocardiogram in nine cats and compared these with the effects of the more toxic compound chlorodifluoromethane in five cats. Inhaled at 60%, trifluoromethane had no effect on cerebral blood flow, the cerebral metabolic rate for oxygen, or oxyhemoglobin content. At 70%, trifluoromethane sensitized the cats' hearts to epinephrine, but to a much lesser degree than 40% chlorodifluoromethane, and produced only moderate changes in cerebral electrical activity as measured by the electroencephalogram. We found trifluoromethane to be suitable for use in animals, but its toxicity needs to be studied further before it can be used in humans for the measurement of cerebral blood flow.     

Neuroimaging using ultrahigh-field magnetic resonance imaging at 7 tesla: current concepts

The introduction of ultrahigh-field MRI at 7 tesla (7T) has increased the interest in the use of neuroimaging techniques in clinical research. The high signal-to-noise ratio and profound susceptibility effect at 7T can remarkably improve the spatial resolution and image contrast of structural imaging, susceptibility imaging, and functional imaging techniques, whereas the heating effects of the radio frequency and the inhomogeneities of the local magnetic field can have substantial negative effects on parameter setting, acquisition time, and image quality. T1 prolongation at 7T can improve the enhancement effects of gadolinium agents and the inflow effects on MR angiography and arterial spin labeling. Ultrahigh-field MRI is expected to have a high clinical impact in the near future; however, further technological advances tailored to ultrahigh-field systems as well as the accumulation of scientific evidence will be needed to establish its clinical significance.     

Regulation of brain blood flow and oxygen delivery in elite breath-hold divers

The roles of involuntary breathing movements (IBMs) and cerebral oxygen delivery in the tolerance to extreme hypoxemia displayed by elite breath-hold divers are unknown. Cerebral blood flow (CBF), arterial blood gases (ABGs), and cardiorespiratory metrics were measured during maximum dry apneas in elite breath-hold divers (n=17). To isolate the effects of apnea and IBM from the concurrent changes on ABG, end-tidal forcing (‘clamp'') was then used to replicate an identical temporal pattern of decreasing arterial PO₂ (PaO₂) and increasing arterial PCO₂ (PaCO₂) while breathing. End-apnea PaO₂ ranged from 23  to 37 mm Hg (30±7 mm Hg). Elevation in mean arterial pressure was greater during apnea than during clamp reaching +54±24% versus 34±26%, respectively; however, CBF increased similarly between apnea and clamp (93.6±28% and 83.4±38%, respectively). This latter observation indicates that during the overall apnea period IBM per se do not augment CBF and that the brain remains sufficiently protected against hypertension. Termination of apnea was not determined by reduced cerebral oxygen delivery; despite 40% to 50% reductions in arterial oxygen content, oxygen delivery was maintained by commensurately increased CBF.     

Fluorocarbon-23 measure of cat cerebral blood flow by nuclear magnetic resonance

We employed fluorocarbon-23 (trifluoromethane) as a nuclear magnetic resonance gaseous indicator of cerebral blood flow in seven cats. Pulsed inhalation of this indicator and switching between two coils allowed the acquisition of both an arterial input and a cerebral response function, making possible multicompartmental curve fits to cerebral uptake and clearance data. The brain:blood partition coefficient for trifluoromethane was 0.9 for both gray and white matter. Fast-compartment blood flows were normal and showed appropriate CO2 reactivity. Slow-compartment blood flows did not demonstrate CO2 reactivity, probably because cranial as well as white-matter blood flows were lumped together in the slow compartment. Although cerebral blood flow was stable during administration of 60% trifluoromethane, the compound did prove to be a mild cardiac sensitizer to epinephrine in five cats.     

Nuclear magnetic resonance study of the immature rat brain

Using rat brains, the maturational change on the water contents and on the proton NMR signals were studied in this laboratory. Water contents, the proton longitudinal relaxation time (T1) and the transverse relaxation time (T2) were measured on the samples from gray and white matters, separately. A constant decrease of these parameter values was observed in relation to the development of the brain. Water content of 1 week-old rat was 88.393 +/- 1.19% in the gray matter (G) and 88.63 +/- 1.96% in the white matter (W). These values decreased gradually and reached adult rat level when the animals became 5 weeks old: 81.47 +/- 1.67% in G and 79.45 +/- 2.39% in W. No marked change on the brain water content was observed thereafter, T1 values of immature (one week-old) rat brain were 1.755 +/- 0.088 sec in G, and 1.832 +/- 0.154 sec in W, while T1 values of the adult rat brain were 1.327 +/- 0.043 sec in G, and 1.297 +/- 0.039 sec in W, respectively. A marked difference was observed on the values of T1 between the immature and the adult rats. T2 value of the 1 week-old rat brain was 101.05 +/- 10.20 msec in G, and 102.75 +/- 8.10 msec in W, respectively. T2 of the mature rat brain was 56.90 +/- 2.61 msec in G, and 54.52 +/- 2.35 msec in W, respectively. A statistically significant correlation was proved between the water content and the proton relaxation time (either T1 and T2).(ABSTRACT TRUNCATED AT 250 WORDS)     

Dextroamphetamine causes a change in regional brain activity in vivo during cognitive tasks: a functional magnetic resonance imaging study of blood oxygen level-dependent response.

BACKGROUND: Dextroamphetamine is known to have profound effects on both subjective and physiologic measurements, but it is unclear to what extent these behavioral changes are a direct result of altered regional brain activation. One method to measure this is to use functional magnetic resonance imaging (fMRI). METHODS: In the present study, fMRI was used to measure both the spatial extent of changes (the number of pixels activated) and the magnitude of the blood oxygen level-dependent (BOLD) response. We examined the effects of motor, verbal, memory, and spatial attention task during fMRI in 18 healthy volunteers. Functional MRI measurements were obtained at baseline and again 75 min after an oral dose of 25 mg dextroamphetamine. RESULTS: Dextroamphetamine caused a decrease in the number of activated pixels and the magnitude of the BOLD response during the three cognitive tasks tested but not during the motor task. These changes were region and task specific. CONCLUSIONS: This is the first study to examine the effect of dextroamphetamine on the number of activated pixels and the BOLD response during the performance of a range of cognitive and motor tasks. Our results suggest that dextroamphetamine causes measurable decreases in brain activity in a variety of regions during cognitive tasks. These changes might be linked to behavioral changes observed after dextroamphetamine administration and could possibly be mediated by alterations in dopaminergic activation.     

31P nuclear magnetic resonance study of the brain in Alzheimer's disease

The histopathological hallmarks of Alzheimer's disease have long been considered to be neurofibrillary tangles (NFT) and neuritic (senile) plaques (SP). Neither of these structures, however, are unique to Alzheimer's disease, and both probably represent end-stage markers of the disorder. NFT have been demonstrated in many disorders; SP occur in small numbers with normal aging. Evidence is presented for elevation of phosphomonoesters (PME) in Alzheimer's brain compared to non-Alzheimer's diseased controls and normal controls. The PME detected by 31P nuclear magnetic resonance (NMR) spectroscopy of autopsy brain are predominantly anabolic precursors of membrane phospholipids. Elevated PME could be secondary to a metabolic block at the rate-limiting enzyme in membrane phospholipid synthesis, which is cytidine triphosphate (CTP): phosphocholine (or phosphoethanolamine) cytidyltransferase (EC 2.7.7.15). Elevated PME could also be secondary to decreased breakdown of PME by phospholipase D activity. Since CTP: phosphocholine cytidyltransferase is inactivated by phosphorylation and since there is independent evidence for hyperphosphorylation of tau and MAP-2 proteins in AD brain, enhanced protein kinase activity could be a common factor. Preliminary evidence suggests that PME could interact with N-methyl-D-aspartate receptors and potentially act as false neurotransmitters. Further studies will be needed to investigate these possibilities.     

N-acetyl-L-aspartate and other amino acid metabolites in Alzheimer's disease brain: a preliminary proton nuclear magnetic resonance study.

We used proton nuclear magnetic resonance spectroscopy in this preliminary study of perchloric acid extracts of 12 Alzheimer's disease (AD) and five control brain samples to measure the relative levels of taurine, aspartate, glutamine, glutamate, gamma-aminobutyric acid (GABA), and the putative neuronal marker, N-acetyl-L-aspartate (NAA). We found no significant changes in taurine, aspartate, or glutamine. NAA was lower in AD compared with control, and this decrease correlated with the number of senile plaques and neurofibrillary tangles in adjacent tissue sections. GABA levels also were lower in AD brain. Glutamate levels were greater in AD than control and showed a close, inverse correlation with NAA levels. These findings suggest that the decrease in NAA reflects neuronal loss and that remaining neurons could be exposed to a relative excess of glutamate and a relative lack of GABA. If present in the neurotransmitter pool, this imbalance could result in neurotoxic cell damage. This hypothesis is further supported by in vitro and in vivo phosphorus 31 nuclear magnetic resonance findings.     

Graded reduction of cerebral blood flow in rat as detected by the nuclear magnetic resonance relaxation time T2: a theoretical and experimental approach.

The ability of transverse nuclear magnetic resonance relaxation time, T2, to reveal acutely reduced CBF was assessed using magnetic resonance imaging (MRI). Graded reduction of CBF was produced in rats using a modification of Pulsinelli's four-vessel occlusion model. The CBF in cerebral cortex was quantified using the hydrogen clearance method, and both T2 and the trace of the diffusion tensor (Dav = 1/3TraceD) in the adjacent cortical tissue were determined as a function of reduced CBF at 4.7 T. A previously published theory, interrelating cerebral hemodynamic parameters, hemoglobin, and oxygen metabolism with T2, was used to estimate the effects of reduced CBF on cerebral T2. The MRI data show that T2 reduces in a U-shape manner as a function of CBF, reaching a level that is 2.5 to 2.8 milliseconds (5% to 6%) below the control value at CBF, between 15% and 60% of normal. This reduction could be estimated by the theory using the literature values of cerebral blood volume, oxygen extraction ratio, and precapillary oxygen extraction during compromised CBF. Dav dropped with two apparent flow thresholds, so that a small 11% to 17% reduction occurred between CBF values of 16% to 45% of normal, followed by a precipitous collapse by more than 20% at CBF below 15% of normal. The current data show that T2 can be used as an indicator of acute hypoperfusion because of its ability to indicate blood oxygenation level-dependent phenomena on reduced CBF.     

7 tesla magnetic resonance imaging: A closer look at substantia nigra anatomy in Parkinson's disease

A hallmark of Parkinson's disease (PD) is the progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Dopaminergic denervation is commonly imaged using radiotracer imaging in target structures such as the striatum. Until recently, imaging made only a modest contribution to detecting neurodegenerative changes in the substantia nigra (SN) directly. Histologically, the SN is subdivided into the ventral pars reticulata and the dorsal pars compacta, which is composed of dopaminergic neurons. In humans, dopaminergic neurons, which are known to accumulate neuromelanin, form clusters of cells (nigrosomes) that penetrate deep into the SN pars reticulata (SNr). The SNr contains higher levels of iron than the SNc in normal subjects. Neuromelanin and T2*‐weighted imaging therefore better detect the SNc and the SNr, respectively. The development of ultra‐high field 7 Tesla (7T) magnetic resonance imaging (MRI) provided the increase in spatial resolution and in contrast that was needed to detect changes in SN morphology. 7T MRI allows visualization of nigrosome‐1 as a hyperintense signal area on T2*‐weighted images in the SNc of healthy subjects and its absence in PD patients, probably because of the loss of melanized neurons and the increase of iron deposition. This review is designed to provide a better understanding of the correspondence between the outlines and subdivisions of the SN detected using different MRI contrasts and the histological organization of the SN. The recent findings obtained at 7T will then be presented in relation to histological knowledge. © 2014 International Parkinson and Movement Disorder Society     

Gamma-aminobutyric acid modulates local brain oxygen consumption and blood flow in rat cerebellar cortex.

In the awake brain, the global metabolic rate of oxygen consumption is largely constant, while variations exist between regions dependent on the ongoing activity. This suggests that control mechanisms related to activity, that is, neuronal signaling, may redistribute metabolism in favor of active networks. This study examined the influence of gamma-aminobutyric acid (GABA) tone on local increases in cerebellar metabolic rate of oxygen (CeMR(O(2))) evoked by stimulation of the excitatory, glutamatergic climbing fiber-Purkinje cell synapse in rat cerebellum. In this network, the postsynaptic depolarization produced by synaptic excitation is preserved despite variations in GABAergic tone. Climbing fiber stimulation induced frequency-dependent increases in synaptic activity and CeMR(O(2)) under control conditions. Topical application of the GABA(A) receptor agonist muscimol blocked the increase in CeMR(O(2)) evoked by synaptic excitation concomitant with attenuation of cerebellar blood flow (CeBF) responses. The effect was reversed by the GABA(A) receptor antagonist bicuculline, which also reversed the effect of muscimol on synaptic activity and CeBF. Climbing fiber stimulation during bicuculline application alone produced a delayed undershoot in CeBF concomitant with a prolonged rise in CeMR(O(2)). The findings are consistent with the hypothesis that activity-dependent rises in CeBF and CeMR(O(2)) are controlled by a common feed-forward pathway and provide evidence for modification of cerebral blood flow and CMR(O(2)) by GABA.     

Diffusion magnetic resonance imaging study of a rat hippocampal slice model for acute brain injury.

Diffusion magnetic resonance imaging (MRI) provides a surrogate marker of acute brain pathology, yet few studies have resolved the evolution of water diffusion changes during the first 8 hours after acute injury, a critical period for therapeutic intervention. To characterize this early period, this study used a 17.6-T wide-bore magnet to measure multicomponent water diffusion at high b-values (7 to 8,080 s/mm(2)) for rat hippocampal slices at baseline and serially for 8 hours after treatment with the calcium ionophore A23187. The mean fast diffusing water fraction (Ffast) progressively decreased for slices treated with 10-microM/L A23187 (-20.9 +/- 6.3% at 8 hours). Slices treated with 50-micromol/L A23187 had significantly reduced Ffast 80 minutes earlier than slices treated with 10-microM/L A23187 (P < 0.05), but otherwise, the two doses had equivalent effects on the diffusion properties of tissue water. Correlative histologic analysis showed dose-related selective vulnerability of hippocampal pyramidal neurons (CA1 > CA3) to pathologic swelling induced by A23187, confirming that particular intravoxel cell populations may contribute disproportionately to water diffusion changes observed by MRI after acute brain injury. These data suggest diffusion-weighted images at high b-values and the diffusion parameter Ffast may be highly sensitive correlates of cell swelling in nervous issue after acute injury.     

Temporal evolution of ischemic damage in rat brain measured by proton nuclear magnetic resonance imaging

We studied the effect of focal cerebral ischemia on the "state" of brain water using proton nuclear magnetic resonance imaging. Focal cerebral ischemia was induced in five halothane-anesthetized rats via tandem occlusion of the left common carotid artery and the left middle cerebral artery. The proton transverse relaxation time, the proton density, and the water diffusion coefficient were measured at various times from the same region of brain tissue from 1.5 to 168 hours after occlusion. Early measurements indicated significant changes in the transverse relaxation time (p = 0.004) and water diffusion coefficient (p = 0.002) of ischemic brain tissue compared with a homologous region from the contralateral hemisphere. However, the transverse relaxation time, proton density, and water diffusion coefficient in ischemic brain tissue showed different temporal evolutions over the study period. Diffusion coefficient weighting was superior to relaxation time and proton density weighting for the visualization of early cerebral ischemia. Our data suggest that nuclear magnetic resonance imaging is sensitive in detecting changes in proton-associated parameters during early cerebral ischemia and confirm significant changes (p less than or equal to 0.01) in the temporal evolution of transverse relaxation times, proton densities, and diffusion coefficients following middle cerebral artery occlusion.     

Cerebral blood flow and tissue oxygen saturation in immediate and progressive ischemia in rat brain.

The aim of the present study was to investigate whether immediate ischemia is more harmful to the brain than progressive ischemia. To do so, we examined the correlation between the degree and the process of ischemia using hypobaric hypotension technique, which was used to reduce systemic blood pressure acutely or progressively below the lower threshold of CBF regulation, in rat brain. In Wistar rats (n = 21), global ischemia using bilateral carotid arteries occlusion coupled with hypobaric hypotension was induced by lowering mean arterial blood pressure (MABP) progressively to 55, 45 and 35 mmHg or immediately to 35 mm Hg. Local cerebral blood flow (ICBF) by laser Doppler (LD) flowmetry and tissue hemoglobin oxygen saturation (HbSO2) by a microspectrophotometric method were measured at 25 corresponding locations using a 'scanning' technique which employs a computer-controlled micromanipulator. Regional CBF (rCBF) and rHbSO2 were determined by calculation of the median value from the 25 ICBF and IHbSO2 data. In the 'progressive' group, rCBF and rHbSO2 decreased gradually and reached 12.2 +/- 15.8 LD-units and 44.9% +/- 13.4% at 35 mm Hg of MABP, respectively. In the 'immediate' group, both parameters dropped suddenly to 7.86 +/- 10.6 LD-units (p < 0.01 vs. CBF of the progressive group) and 22.5% +/- 15.5% (p < 0.001 vs. tissue HbSO2 of the progressive group) from the control at 35 mmHg. These data suggested that cerebral ischemia is better tolerated if it is induced gradually. CBF recorded by LD-scanning technique and HbSO2 value by microspectrophotometric method correlated well in the ischemic condition, indicating that HbSO2 can be preserved if CBF is decreased gradually.     

Quantitative assessment of the balance between oxygen delivery and consumption in the rat brain after transient ischemia with T2 -BOLD magnetic resonance imaging.

The balance between oxygen consumption and delivery in the rat brain after exposure to transient ischemia was quantitatively studied with single-spin echo T2-BOLD (blood oxygenation level-dependent) magnetic resonance imaging at 4.7 T. The rats were exposed to graded common carotid artery occlusions using a modification of the four-vessel model of Pulsinelli. T2, diffusion, and cerebral blood volume were quantified with magnetic resonance imaging, and CBF was measured with the hydrogen clearance method. A transient common carotid artery occlusion below the CBF value of approximately 20 mL x 100 g(-1) x min(-1) was needed to yield a T2 increase of 4.6 +/- 1.2 milliseconds (approximately 9% of cerebral T2) and 6.8 +/- 1.7 milliseconds (approximately 13% of cerebral T2) after 7 and 15 minutes of ischemia, respectively. Increases in CBF of 103 +/- 75% and in cerebral blood volume of 29 +/- 20% were detected in the reperfusion phase. These hemodynamic changes alone could account for only approximately one third of the T2 increase in luxury perfusion, suggesting that a substantial increase in blood oxygen saturation (resulting from reduced oxygen extraction by the brain) is needed to explain the magnetic resonance imaging observation.     

Measuring cerebral blood flow using magnetic resonance imaging techniques.

Magnetic resonance imaging techniques measuring CBF have developed rapidly in the last decade, resulting in a wide range of available methods. The most successful approaches are based either on dynamic tracking of a bolus of a paramagnetic contrast agent (dynamic susceptibility contrast) or on arterial spin labeling. This review discusses their principles, possible pitfalls, and potential for absolute quantification and outlines clinical and neuroscientific applications.     

Simultaneous blood oxygenation level-dependent and cerebral blood flow functional magnetic resonance imaging during forepaw stimulation in the rat.

The blood oxygenation level-dependent (BOLD) contrast mechanism can be modeled as a complex interplay between CBF, cerebral blood volume (CBV), and CMRO2. Positive BOLD signal changes are presumably caused by CBF changes in excess of increases in CMRO2. Because this uncoupling between CBF and CMRO2 may not always be present, the magnitude of BOLD changes may not be a good index of CBF changes. In this study, the relation between BOLD and CBF was investigated further. Continuous arterial spin labeling was combined with a single-shot, multislice echo-planar imaging to enable simultaneous measurements of BOLD and CBF changes in a well-established model of functional brain activation, the electrical forepaw stimulation of alpha-chloralose-anesthetized rats. The paradigm consisted of two 18- to 30-second stimulation periods separated by a 1-minute resting interval. Stimulation parameters were optimized by laser Doppler flowmetry. For the same cross-correlation threshold, the BOLD and CBF active maps were centered within the size of one pixel (470 microm). However, the BOLD map was significantly larger than the CBF map. Measurements taken from 15 rats at 9.4 T using a 10-millisecond echo-time showed 3.7 +/- 1.7% BOLD and 125.67 +/- 81.7% CBF increases in the contralateral somatosensory cortex during the first stimulation, and 2.6 +/- 1.2% BOLD and 79.3 +/- 43.6% CBF increases during the second stimulation. The correlation coefficient between BOLD and CBF changes was 0.89. The overall temporal correlation coefficient between BOLD and CBF time-courses was 0.97. These results show that under the experimental conditions of the current study, the BOLD signal changes follow the changes in CBF.