Simultaneous acquisition of gradient echo/spin echo BOLD and perfusion with a separate labeling coil

Arterial spin labeling‐based cerebral blood flow imaging complements blood oxygenation level dependent (BOLD) imaging with a measure that is more quantitative and has better specificity to neuronal activation. Relative to gradient echo BOLD, spin echo BOLD has better spatial specificity because it is less biased to large draining veins. Although there have been many studies comparing simultaneously acquired cerebral blood flow data with gradient echo BOLD data in fMRI, there have been few studies comparing cerebral blood flow with SE BOLD and no study comparing all three. We present a pulse sequence that simultaneously acquires cerebral blood flow data with a separate labeling coil, gradient echo BOLD, and spin echo BOLD images. Simultaneous acquisition avoids interscan variability, allowing more direct assessment and comparison of each contrast's relative specificity and reproducibility. Furthermore, it facilitates studies that may benefit from multiple complementary measures. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Characterization of effects of mean arterial blood pressure induced by cocaine and cocaine methiodide on BOLD signals in rat brain.

A total of 45 male Sprague-Dawley rats were employed to determine whether cocaine or cocaine methiodide (CM) administration can induce a significant increase in mean arterial blood pressure (MABP) in rats, and whether such an increase in MABP can produce a global increase in blood oxygenation level-dependent (BOLD) contrast in the rat brain detectable by functional magnetic resonance imaging (fMRI). Cocaine methiodide is a quaternary derivative of cocaine that shares the same cardiovascular effects of cocaine, but does not penetrate the blood-brain barrier (BBB). Experimental results demonstrated that both CM (with doses of 2.5 and 7.5 mg/kg) and cocaine (with doses of 1.25 and 5.0 mg/kg) can induce a significant MABP change (30-80%). It was found that CM can only produce scattered, weak, and transient BOLD signals in a few voxels of the rat brain, and that these MABP-induced BOLD signals are not dose-dependent. In contrast, the administration of cocaine induced dose-dependent biphasic BOLD signals that were consistent with pharmacologically-induced cerebral vascular constriction and neuronal activity in the mesolimbic systems of the rat brain. The potential confounding factor of the MABP changes had little effect on the interpretation of drug-induced BOLD signal changes. These results confirm that the BOLD-weighted fMRI method can be extended to map drug-induced neuronal activity.     

Functional magnetic resonance imaging of the human brain based on signal enhancement by extravascular protons (SEEP fMRI).

Functional magnetic resonance imaging (fMRI) studies of the human brain were carried out at 3 Tesla to investigate an fMRI contrast mechanism that does not arise from the blood oxygen-level dependent (BOLD) effect. This contrast mechanism, signal enhancement by extravascular protons (SEEP), involves only proton-density changes and was recently demonstrated to contribute to fMRI signal changes in the spinal cord. In the present study it is hypothesized that SEEP fMRI can be used to identify areas of neuronal activity in the brain with as much sensitivity and precision as can be achieved with BOLD fMRI. A detailed analysis of the areas of activity, signal intensity time courses, and the contrast-to-noise ratio (CNR), is also presented and compared with the BOLD fMRI results. Experiments were carried out with subjects performing a simple finger-touching task, or observing an alternating checkerboard pattern. Data were acquired using a conventional BOLD fMRI method (gradient-echo (GE) EPI, TE = 30 ms), a conventional method with reduced BOLD sensitivity (GE-EPI, TE = 12 ms), and SEEP fMRI (spin-echo (SE) EPI, TE = 22 ms). The results of this study demonstrate that SEEP fMRI may provide better spatial localization of areas of neuronal activity, and a higher CNR than conventional BOLD fMRI, and has the added benefit of lower sensitivity to field inhomogeneities.     

BOLD fMRI of the visual cortex: quantitative responses measured with a graded stimulus at 1.5 Tesla

PURPOSE: To measure and quantitatively characterize an activity generated by the neurons of the visual cortex (VC) in response to graded luminous intensity contrast stimuli using a 1.5 Tesla scanner. MATERIALS AND METHODS: Functional magnetic resonance imaging (fMRI) of the vc with the intrinsic blood oxygenation level dependent (BOLD) mechanism was performed by using a paradigm with a 5 x 5 flashing checkerboard pattern flickering eight times per second at eight luminance contrasts presented in a randomized order. The changes of the luminance contrast were obtained by varying the luminance intensity of the white checkerboard squares. Each of eight trials, corresponding to eight luminance contrasts, consisted of six "rest" and six "activation" epochs, repeated five times, amounting to 60 measurement periods per trial. During each epoch, 10 contiguous oblique axial-to-coronal slices covering the calcarine fissure region and parallel to a line through the anterior-posterior commissure (AC-PC) markers were acquired using a gradient-recalled echo planar imaging (GRE-EPI) sequence. RESULTS: The measurements showed changes in the activation extent in the VC following the stimulus' rising luminance intensity contrast. In addition, the fMRI signal in those activated areas present throughout all eight trials, referred to as "common" voxels in this report, showed an increasing trend as a function of the rising luminance intensity contrast. CONCLUSION: These results suggest that the processes of the neuronal recruitment that affects the extent and number of activated neurons, and the neuronal enhancement that defines the magnitude of the neuronal activation are dependent on the luminance intensity contrast. These changes can be visualized and quantified using BOLD fMRI at 1.5 Tesla.     

Titration of the BOLD effect: separation and quantitation of blood volume and oxygenation changes in the human cerebral cortex during neuronal activation and ferumoxide infusion.

Most functional magnetic resonance imaging (fMRI) techniques are sensitive to susceptibility variations and rely on the change in blood oxygenation level in response to neuronal activation (BOLD). The BOLD effect is accompanied by a change in cerebral blood flow (rCBF) and cerebral blood volume (rCBV). Intravascular contrast agents, such as magnetite nanoparticles, can be used to measure changes in rCBV. A new measuring protocol has been developed that enables the separate quantification of changes in blood volume and oxygenation levels. A combination of alternating acoustic stimulation blocks and infusion of a superparamagnetic contrast agent offers the possibility to disentangle the competing influences of oxygenation and blood volume changes. Serial blood sampling during infusion was used to assess the actual contrast agent concentration during infusion in order to calculate absolute blood volume changes during neuronal resting and activation states. Magn Reson Med 42:829-836, 1999.     

Spatial and temporal characteristics of physiological noise in fMRI at 3T

RATIONALE AND OBJECTIVES: Physiological noise in blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) has been shown to have characteristics similar to the BOLD signal itself, suggesting that it may have a vascular dependence. In this study, we evaluated the influence of physiological noise in fMRI as revealed by the differences in vasculature sensitivity of gradient-echo echo-planar imaging (GE-EPI) and spin-echo EPI (SE-EPI). MATERIALS AND METHODS: The contribution of physiological noise to the fMRI signal during activation of the visual cortex was assessed by comparing its temporal characteristics with respect to echo time (TE), using both GE-EPI and SE-EPI. The correlation of the noise in fMRI with apparent diffusion coefficient (ADC) and the number of components required to describe its variance, as determined by principal-component analysis (PCA), were also assessed. RESULTS: The SE-EPI data were less affected by a TE-dependence of noise, in contrast to the apparent physiological noise in GE-EPI. Voxel-wise analysis revealed that total apparent noise increased as ADC values increased, and the relationship was different for GE-EPI and SE-EPI. PCA revealed that while the number of components characterizing the noise in SE-EPI data increased in a TE-dependent manner, approaching that of white noise at long echo time, the number of components from GE-EPI data was TE-independent. CONCLUSIONS: The difference in sensitivities to physiological noise between SE-EPI and GE-EPI suggests that extravascular BOLD processes around draining veins contribute significantly to physiological noise in BOLD fMRI, and the suppression of this noise component may enhance SE-EPI BOLD sensitivity at higher fields.     

Innovations in functional MR imaging of the brain: arterial spin labeling and diffusion

The standard technique for brain activation functional MRI (fMRI) is the BOLD sequence. Two new techniques have emerged: arterial spin labeling (ASL) MRI and diffusion MRI. Both have the theoretical advantage of more accurately directly demonstrating neuronal activation compared to BOLD imaging, resulting in improved spatial and temporal resolution. ASL is a perfusion sequence using labeled arterial protons as an endogenous perfusion agent. In spite of methodological difficulties, quantitative CBF measurements are possible. ASL is less susceptible to venous contamination than BOLD and more reproducible. Diffusion MRI evaluates neuronal activation at the cellular level with the prospect of excellent spatial resolution. The main limitations for both techniques are the technical difficulties in the acquisition and the low SNR. AS such, ASL is not widely used clinically and diffusion remains in the field of research. However, the increasing availability of 3T MR systems coupled with multi-channel surface coils and improved postprocessing techniques should improve the detection of the brain activation signal. It is thus possible that these techniques could become clinically available either in complement to or as a replacement for BOLD imaging.     

Spatial correlations of laminar BOLD and CBV responses to rat whisker stimulation with neuronal activity localized by Fos expression.

The spatial relationship between a measured fMRI signal and its underlying neuronal activity remains unclear. One obstacle is the localization of neuronal activity; another is the spatial resolution of fMRI. In the present study, high-resolution BOLD and CBV fMRI experiments (voxel size: 156 x 156 x 2000 microm3) were conducted in the rat whisker barrel cortex at 3 T; neuronal activity across cortical layers was mapped using the Fos expression technique. Results show that BOLD response is weighted by blood volume and that pixels with high BOLD response can be located at the cortical surface or in deep layers, depending on local vasculature. In contrast to BOLD response, the pixels with high CBV response were consistently clustered in the deep cortical layers. Percentage-CBV change in cortical layers IV-V was 7.3 +/- 1.5%, which was significantly higher than in layers I-III (4.1 +/- 0.9%) and VI (4.3 +/- 0.7%) (mean +/- SEM). The laminar distribution of CBV response correlates well with neuronal activity localized by Fos expression. We conclude that neuronal activity can be inferred from CBV fMRI data with high spatial accuracy. The data indicate that both intracolumn functional connectivity and neurovascular coupling can be studied using CBV fMRI.     

The interaction between magnetization transfer and blood-oxygen-level-dependent effects.

Low-power off-resonance spin-echo magnetization transfer (MT) imaging experiments with a long repetition time (TR) were performed on rat brain for a range of arterial PCO2 levels. The measured magnetization transfer ratio decreased with increased arterial PCO2 levels. When performing blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI)-type data analysis in which signal intensities were normalized to the normocapnic state, the CO2-based BOLD effect was much stronger with than without saturation. This increased effect is a consequence of the fact that the MT effect reduces the signal intensity in tissue more than in blood, thereby amplifying the contribution of the intravascular BOLD signal change to the overall BOLD effect. The results offer a potential approach to measure absolute cerebral blood volume in vivo and to amplify the BOLD effects for fMRI studies.     

Disparity of activation onset in sensory cortex from simultaneous auditory and visual stimulation: Differences between perfusion and blood oxygenation level-dependent functional magnetic resonance imaging

PURPOSE: To compare the temporal behaviors of perfusion and blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in the detection of timing differences between distinct brain areas, and determine potential latency differences between stimulus onset and measurable fMRI signal in sensory cortices. MATERIALS AND METHODS: Inversion recovery (IR) spin-echo echo-planar imaging (EPI) and T2*-weighted gradient-echo EPI sequences were used for perfusion- and BOLD-weighted experiments, respectively. Simultaneous auditory and visual stimulations were employed in an event-related (ER) paradigm. Signal time courses were averaged across 40 repeated trials to evaluate the onset of activation and to determine potential differences of activation latency between auditory and visual cortices and between these scanning methods. RESULTS: Temporal differences between visual and auditory areas ranged from 90-200 msec (root-mean-square (RMS) = 134 msec) and from -80 to 930 msec (RMS = 604 msec) in perfusion and BOLD measurements, respectively. The temporal variability detected with BOLD sequences was larger between subjects and was significantly greater than that in the perfusion response (P < 0.04). The measured time to half maximum (TTHM) values for perfusion imaging (visual, 3260 +/- 710 msec; auditory, 3130 +/- 700 msec) were earlier than those in BOLD responses (visual, 3770 +/- 430 msec; auditory, 3360 +/- 460 msec). CONCLUSION: The greater temporal variability between brain areas detected with BOLD could result from differences in the venous contributions to the signal. The results suggest that perfusion methods may provide more accurate timing information of neuronal activities than BOLD-based imaging.     

听觉性语言刺激的功能磁共振成像研究

目的用MR血氧水平依赖性(BOLD)技术研究听觉语言的功能磁共振成像(fMRI)。资料与方法23例受试者，其中正常志愿者14例，脑肿瘤患者6例，脑外伤软化灶形成患者3例。进行听觉性语言刺激共25次，采用BOLD技术进行相应脑功能区成像。结果所有受试者均能在MRI检查中表现出局部脑功能活动区规律的信号强度-时间变化曲线，并获得较清晰的图像。功能区附近的占位病变可造成局部功能区的移位和缩小等改变。结论BOLD-fMRI在活体人脑听觉语言的功能区定位方面是一种有效的方法。对需实施手术的颅内占位。病变进行BOLD-MRI检查对指导手术有价值。     

Dynamic characteristics of oxygenation-sensitive MRI signal in different temporal protocols for imaging human brain activity

The temporal characteristics of cerebral blood oxygenation during human brain activation were monitored with dynamic echo-planar imaging (EPI) using the blood oxygenation level dependent (BOLD) fMRI. We investigated oxygenation-sensitive signal changes: 1. during repetitive block stimuli, to determine the latency of the activation-induced signal change in the primary visual cortex; 2. on shortening the rest periods between constant stimulated phases, to investigate the limitations that this latency poses in temporal resolution of the technique; and 3. on sustained steady-state stimulation, to characterise oxygenation changes during prolonged brain activation using different stimuli. Delayed intrinsic haemodynamic response and a finite signal-to-noise ratio limit the temporal resolution achieved with BOLD fMRI. Separate activation periods were resolved when the delay between consecutive stimulations was at least 2 s. In this study oxygenation remained elevated throughout sustained activation, suggesting a constant rate of oxygen consumption by the primary cortical neurones during activation. Characterisation of fMRI signal dynamics in dynamic temporal protocols is significant both in terms of optimising stimulation protocols and the potential to gain insight into the physiological mechanisms underlying neuronal activation which could increase the clinical applicability of the technique. Received: 13 September 1999 Accepted: 10 November 1999     

Arterial spin labeling perfusion fMRI with very low task frequency.

Functional magnetic resonance imaging (fMRI) has become the most widely used modality for visualizing regional brain activation in response to sensorimotor or cognitive tasks. While the majority of fMRI studies have used blood oxygenation level-dependent (BOLD) contrast as a marker for neural activation, baseline drift effects result in poor sensitivity for detecting slow variations in neural activity. By contrast, drift effects are minimized in arterial spin labeling (ASL) perfusion contrast, primarily as a result of successive pairwise subtraction between images acquired with and without labeling. Recent data suggest that ASL contrast shows stable noise characteristics over the entire frequency spectrum, which makes it suitable for studying low-frequency events in brain function. The present study investigates the relative sensitivities of ASL and BOLD contrast in detecting changes in motor cortex activation over a spectrum of frequencies of experimental design, where the alternating period between the resting state and activation is varied from 30 s up to 24 hr. The results demonstrate that 1) ASL contrast can detect differences in motor cortex activation over periods of minutes, hours, and even days; 2) the functional sensitivity of ASL contrast becomes superior to that of BOLD contrast when the alternating period between the resting state and activation is greater than a few minutes; and 3) task activation measured by ASL tends to have less intersubject variability than BOLD contrast. The improved sensitivity of the ASL contrast for low task frequency and longitudinal studies, along with its superior power in group analysis, is expected to extend the range of experimental designs that can be studied using fMRI.     

Combining EEG and fMRI: a multimodal tool for epilepsy research

Patients with epilepsy often present in their electroencephalogram (EEG) short electrical potentials (spikes or spike-wave bursts) that are not accompanied by clinical manifestations but are of important diagnostic significance. They result from a population of abnormally hyperactive and hypersynchronous neurons. It is not easy to determine the location of the cerebral generators and the other brain regions that may be involved as a result of this abnormal activity. The possibility to combine EEG recording with functional MRI (fMRI) scanning opens the opportunity to uncover the regions of the brain showing changes in the fMRI signal in response to epileptic spikes seen in the EEG. These regions are presumably involved in the abnormal neuronal activity at the origin of epileptic discharges. This paper reviews the methodology involved in performing such studies, particularly the challenge of recording a good quality EEG inside the MR scanner while scanning is taking place, and the methods required for the statistical analysis of the combined EEG and fMRI time series. We review the results obtained in patients with different types of epileptic disorders and discuss the difficult theoretical problems raised by the interpretation of an increase (activation) and decrease (deactivation) in blood oxygen level dependent (BOLD) signal, both frequently seen in response to spikes.     

Functional MRI in human motor control studies and clinical applications.

Functional magnetic resonance imaging (fMRI) has been a useful tool for the noninvasive mapping of brain function associated with various motor and cognitive tasks. Because fMRI is based on the blood oxygenation level dependent (BOLD) effect, it does not directly record neural activity. With the fMRI technique, distinguishing BOLD signals created by cortical projection neurons from those created by intracortical neurons appears to be difficult. Two major experimental designs are used in fMRI studies: block designs and event-related designs. Block-designed fMRI presupposes the steady state of regional cerebral blood flow and has been applied to examinations of brain activation caused by tasks requiring sustained or repetitive movements. By contrast, the more recently developed event-related fMRI with time resolution of a few seconds allows the mapping of brain activation associated with a single movement according to the transient aspects of the hemodynamic response. Increasing evidence suggests that multiple motor areas are engaged in a networked manner to execute various motor acts. In order to understand functional brain maps, it is important that one understands sequential and parallel organizations of anatomical connections between multiple motor areas. In fMRI studies of complex motor tasks, elementary parameters such as movement length, force, velocity, acceleration and frequency should be controlled, because inconsistency in those parameters may alter the extent and intensity of motor cortical activation, confounding interpretation of the findings obtained. In addition to initiation of movements, termination of movements plays an important role in the successful achievement of complex movements. Brain areas exclusively related to the termination of movements have been, for the first time, uncovered with an event-related fMRI technique. We propose the application of fMRI to the elucidation of the pathophysiology of movement disorders, particularly dystonia, which exhibits involuntary co-contraction of agonist and antagonist muscles and manifests abnormal posture or slow repetition of movements.     

Systemic theophylline augments the blood oxygen level-dependent response to forepaw stimulation in rats

BACKGROUND AND PURPOSE: Functional MR imaging with blood oxygen level-dependent (BOLD) contrast enhancement is believed to rely on changes in cerebral blood flow and deoxyhemoglobin level to estimate the location and degree of neural activation. We studied the relationship between neural activation and the observed BOLD response by using theophylline, an antagonist of the inhibitory neurotransmitter adenosine and a potent inhibitor of the vasodilatory response to neural activation. METHODS: Using a rat model with electrical forepaw stimulation, we performed fMRI measurements before and after the systemic injection of either theophylline (0.1 mmol/kg) or an equivalent volume of saline. Changes in the BOLD response were quantified by determining the number of activated voxels and the amplitude of the BOLD response for each animal in the theophylline and saline groups. RESULTS: The theophylline group had a significantly Tincreased BOLD response (70-150% increased activated voxel count and 60-65% increased BOLD response amplitude) at 45 and 60 minutes after systemic injection compared with baseline. The response of the saline-injected control group did not change significantly. CONCLUSION: The administration of systemic theophylline significantly augmented the BOLD response due to either an elevation of resting deoxyhemoglobin levels or the neuroexcitatory effect of theophylline. This effect potentially could be used in human fMRI studies to increase the sensitivity of the BOLD response.     

Detecting activations in event-related fMRI using analysis of variance.

The most common design of a functional MRI (fMRI) experiment is a block design. The use of rapid imaging, however, and carefully designed paradigms makes the separation of cognitive events possible. Such experiments make use of event-related paradigms, in which a task involving several cognitive processes is repeated. In analyzing data from such experiments, existing methods often prove inadequate, because the prediction of the exact shape or timing of the time course is difficult. Here we present an analysis of variance (ANOVA) method for analyzing fMRI data that does not require any assumptions about the shape of the activation time course. Consequently, this method can simultaneously detect brain areas showing a variety of stimulus-locked time courses in the same experiment. The utility of this technique is demonstrated by the analysis of data from two event-related paradigms in which regions of activation are detected that correspond to a variety of distinct neural processes, yielding significantly different temporal signal changes. Magn Reson Med 42:1117-1122, 1999.     

Comparison of the BOLD- and EPISTAR-technique for functional brain imaging by using signal detection theory

Two magnetic resonance imaging techniques, BOLD (blood oxygenation level dependent) and EPISTAR (echo-planar imaging and signal targeting with alternating radio-frequency), were compared for functional brain imaging. Ten volunteers were imaged performing a sequential finger to thumb opposition task alternating with no movement conditions. Techniques were compared using variance maps and signal detection theory (ROC analysis). True positive activation in regions of interest with expected task-dependent signal changes were computed versus false activation rates in regions in which no activation was expected. D-prime coefficients were calculated for each comparison and statistically compared using a paired t test. Activation in the perirolandic region was seen in all volunteers with both techniques. There was no significant difference for the d-prime between BOLD and EPISTAR. These results indicate that based on a different physiologic principle, EPISTAR is an alternative to BOLD to perform fMRI with similar results.     

Application of parallel imaging to fMRI at 7 Tesla utilizing a high 1D reduction factor.

Gradient-echo EPI, blood oxygenation level-dependent (BOLD) functional MRI (fMRI) using parallel imaging (PI) is demonstrated at 7 Tesla with 16 channels, a fourfold 1D reduction factor (R), and fourfold maximal aliasing. The resultant activation detection in finger-tapping fMRI studies was robust, in full agreement with expected activation patterns based on prior knowledge, and with functional maps generated from full field of view (FOV) coverage of k-space using segmented acquisition. In all aspects the functional maps acquired with PI outperformed segmented coverage of full k-space. With a 1D R of 4, fMRI activation based on PI had higher statistical significance, up to 1.6-fold in an individual case and 1.25+/-.25 (SD) fold when averaged over six studies, compared to four-segment/full-FOV data in which the square root R reduction in the image signal-to-noise ratio (SNR) due to k-space undersampling was compensated for by acquiring additional repetitions of the undersampled k-space. When this compensation for loss in SNR was not performed, the effect of PI was determined by the ratio of physiologically induced vs. intrinsic (thermal) noise in the fMRI time series and the extent to which physiological "noise" was amplified by the use of segmentation in the full-FOV data. The results demonstrate that PI is particularly beneficial at this ultrahigh field strength, where both the intrinsic image SNR and temporal signal fluctuations due to physiological processes are large.     

Anesthetic effects on regional CBF,BOLD, and the coupling between task‐induced changes in CBF and BOLD: An fMRI study in normal human subjects

Functional MR imaging was performed in sixteen healthy human subjects measuring both regional cerebral blood flow (CBF) and blood oxygen level dependent (BOLD) signal when visual and auditory stimuli were presented to subjects in the presence or absence of anesthesia. During anesthesia, 0.25 mean alveolar concentration (MAC) sevoflurane was administrated. We found that low‐dose sevoflurane decreased the task‐induced changes in both BOLD and CBF. Within the visual and auditory regions of interest inspected, both baseline CBF and the task‐induced changes in CBF decreased significantly during anesthesia. Low‐dose sevoflurane significantly altered the task‐induced CBF‐BOLD coupling; for a unit change of CBF, a larger change in BOLD was observed in the anesthesia condition than in the anesthesia‐free condition. Low‐dose sevoflurane was also found to have significant impact on the spatial nonuniformity of the task‐induced coupling. The alteration of task‐induced CBF‐BOLD coupling by low‐dose sevoflurane introduces ambiguity to the direct interpretation of functional MRI (fMRI) data based on only one of the indirect measures—CBF or BOLD. Our observations also indicate that the manipulation of the brain with an anesthetic agent complicates the model‐based quantitative interpretation of fMRI data, in which the relative task‐induced changes in oxidative metabolism are calculated by means of a calibrated model given the relative changes in the indirect vascular measures, usually CBF and BOLD. Magn Reson Med 60:987–996, 2008. © 2008 Wiley‐Liss, Inc.