Dynamic functional imaging of relative cerebral blood volume during rat forepaw stimulation

Dynamic measurements of regional changes in cerebral blood volume (CBV) were performed in rat models of hypercarbia and focal neuronal activation using T₂-weighted imaging after injection of an intravascular contrast agent with a very long blood half-life. Calculated percent CBV change during hypercarbia was consistent with literature results from other non-invasive modalities. Equivalent percent CBV increases were found using spin- and gradient-echo images, suggesting proportional changes in blood volume for capillaries and small veins. During electrical stimulation of rat forepaw, focal CBV response to stimulation (24 ± 4%) was significantly delayed relative to blood oxygen level dependent (BOLD) signal after both onset and cessation of stimulation. Poststimulus CBV decay was temporally consistent with the BOLD poststimulus undershoot. The use of exogenous agent increased the functional contrast-to-noise ratio relative to BOLD imaging by 5.7 ± 1.3 at a magnetic field strength of 2 Tesla and 1.5 ± 0.2 at 4.7 Tesla.     

Exogenous contrast agent improves sensitivity of gradient-echo functional magnetic resonance imaging at 9.4 T.

Relative to common clinical magnetic field strengths, higher fields benefit functional brain imaging both by providing additional signal for high-resolution applications and by improving the sensitivity of endogenous contrast due to the blood oxygen level dependent (BOLD) mechanism, which has limited detection power at low magnetic fields relative to the use of exogenous contrast agent. This study evaluates the utility of iron oxide contrast agent for gradient echo functional MRI at 9.4 T in rodents using cocaine and methylphenidate as stimuli. Relative to the BOLD method, the use of high iron doses and short echo times provided a roughly twofold global increase in functional sensitivity, while also suppressing large vessel signal and reducing susceptibility artifacts. Furthermore, MRI measurements of the functional percentage change in cerebral blood volume (CBV) showed excellent agreement with results obtained at much lower magnetic field strengths, demonstrating that MRI estimates of this quantity are roughly independent of magnetic field when appropriate techniques are employed. The derived field dependencies for relative sensitivity and MRI estimates of the percentage change in CBV suggest that the benefits provided by exogenous agents will persist even at much higher magnetic fields than 9.4 T.     

Functional connectivity in blood oxygenation level‐dependent and cerebral blood volume‐weighted resting state functional magnetic resonance imaging in the rat brain

Purpose:

To directly compare functional connectivity and spatiotemporal dynamics acquired with blood oxygenation level‐dependent (BOLD) and cerebral blood volume (CBV)‐weighted functional magnetic resonance imaging (fMRI) in anesthetized rats.

Materials and Methods:

A series of BOLD images were acquired in 10 rats followed by CBV‐weighted images created by injection of ultrasmall iron oxide particles. Functional connectivity, spectral information, and spatiotemporal dynamics were compared for the BOLD and CBV‐weighted resting state scans.

Results:

BOLD scans exhibited higher cross‐correlation values compared to CBV‐weighted scans, but the spatial patterns of correlation were similar. The BOLD spectrum contains power evenly distributed throughout the low‐frequency range while the CBV power spectrum exhibited a high power peak localized to ≈0.2 Hz. Both BOLD and CBV resting state scans showed similar propagating waves of activity along the cortex from the SII toward MI; however, these waves were detected more often in BOLD scans than in CBV scans.

Conclusion:

While the power spectrum of the CBV signal is different from that of the BOLD signal, both connectivity maps and spatiotemporal dynamics are similar for the two modalities. Further experiments should address the relationship between spontaneous neural activity, local changes in metabolism, and hemodynamic fluctuations to elucidate the origins of the BOLD and CBV signals. J. Magn. Reson. Imaging 2010;32:584–592. © 2010 Wiley‐Liss, Inc.     

Functional imaging of the parotid glands using blood oxygenation level dependent (BOLD)-MRI at 1.5T and 3T

PURPOSE: To evaluate the function of the parotid glands before and during gustatory stimulation, using an intrinsic susceptibility-weighted MRI method (blood oxygenation level dependent, BOLD-MRI) at 1.5T and 3T. MATERIALS AND METHODS: A total of 10 and 13 volunteers were investigated at 1.5T and 3T, respectively. Measurements were performed before and during gustatory stimulation using ascorbate. Circular regions of interest (ROIs) were delineated in the left and right parotid glands, and in the masseter muscle for comparison. The effects of stimulation were evaluated by calculating the difference between the relaxation rates, DeltaR(2)*. Baseline and stimulation were statistically compared (Student's t-tests), merging both parotid glands. RESULTS: The averaged DeltaR(2)* values prestimulation obtained in all parotid glands were stable (-0.61 to 0.38 x 10(-3) seconds(-1)). At 3T, these values were characterized by an initial drop (to -2.7 x 10(-3) seconds(-1)) followed by a progressive increase toward the baseline. No significant difference was observed between baseline and parotid gland stimulation at 1.5T, neither for the masseter muscle at both field strengths. A considerable interindividual variability (over 76%) was noticed at both magnetic fields. CONCLUSION: BOLD-MRI at 3T was able to detect DeltaR(2)* changes in the parotid glands during gustatory stimulation, consistent with an increase in oxygen consumption during saliva production.     

Improved mapping of pharmacologically induced neuronal activation using the IRON technique with superparamagnetic blood pool agents.

The use of functional magnetic resonance imaging (fMRI) techniques for evaluation of pharmacologic stimuli has great potential for understanding neurotransmitter dynamics for a number of brain disorders, such as drug abuse, schizophrenia, epilepsy, or neurodegeneration. Unfortunately, blood oxygenation level-dependent (BOLD) imaging at common fields strengths, such as 1.5 or 3 T, has very low sensitivity and contrast-to-noise ratios (CNRs). We demonstrate here the utility of using an intravascular superparamagnetic iron oxide contrast agent with a long plasma half-life for evaluation of hemodynamic changes related to dopaminergic stimuli using amphetamine or the cocaine analog 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT). We refer to this technique as increased relaxation with iron oxide nanoparticles (IRON). Results obtained here show that even at field strengths as high as 4.7 T, one can obtain increases in CNR by factors of 2-3 over BOLD imaging that lead to greater than an order of magnitude increase in statistical power with greatly increased sensitivity to hemodynamic changes in brain regions difficult to observe using BOLD imaging. Furthermore, use of the intravascular contrast agent allows for a meaningful physiologic parameter to be measured (relative cerebral blood volume (rCBV)), compared to conventional BOLD imaging.     

A comparison between blood oxygenation level-dependent and cerebral blood volume contrast in the rat cerebral and cerebellar somatosensoric cortex during electrical paw stimulation

PURPOSE: To implement and optimize cerebral blood volume (CBV)-weighted functional magnetic resonance imaging (fMRI) in the rat cerebral and cerebellar cortex during electrical paw stimulation. MATERIALS AND METHODS: fMRI of the cerebral and cerebellar cortex was performed during electrical paw stimulation on a 7-T MRI system (MRRS, Guilford, UK) comparing the blood oxygenation level-dependent (BOLD) and CBV-weighted contrast with different ultrasmall particles of iron oxide (USPIO) contrast doses (NC100150, 30 mg Fe/mL; Amersham Health, Oslo, Norway) and different TE. RESULTS: Doses of 15 and 20 mg/kg USPIO at TE = T*2 or TE = 14 msec almost doubled the contrast-to-noise ratio (CNR) of the activated areas in the cerebral cortex without affecting the overall signal-to-noise ratio (SNR) or the incidence of activation (100%). In the cerebellum the SNR decreased significantly with an increasing contrast dose. At a dose of 15 mg/kg, the CNR was slightly smaller than the CNR measured in the BOLD images, but the activation incidence seemed to be doubled. At 20 mg/kg, the CNR was slightly increased, but the activation incidence was lower. At both contrast doses the venous artifacts disappeared. CONCLUSION: A USPIO contrast dose of 20 mg/kg proved to be beneficial for fMRI in the rat, even though it affected the CNR and SNR in the cerebral and the cerebellar cortex differentially.     

T1-weighted functional imaging based on a contrast agent in presurgical mapping

Purpose

To assess the applicability of T1‐weighted images in the presence of a contrast agent for functional mapping free of susceptibility artifacts, in comparison to the blood oxygenation level‐dependent (BOLD) imaging.

Materials and Methods

Six patients and five control subjects were scanned using BOLD and T1‐weighted functional imaging, in the presence of a Gd‐DTPA contrast‐agent (TOFICA). In the control group, low‐ and high‐resolution BOLD images were performed. Functional stimuli included motor and language activations.

Results

Both BOLD and TOFICA methods resulted in activations in the expected anatomical regions. The TOFICA mapping gave less distributed and with higher percent signal changes in comparison with the BOLD images. Gd‐DTPA remained almost constant in the blood for at least 15 min post injection. In one patient with surgical clips, no signal was detected in the left cerebral hemisphere using BOLD imaging, but activation could be mapped using the TOFICA method.

Conclusion

T1‐weighted imaging in the presence of a contrast agent can be used for functional mapping. This method is insensitive to susceptibility artifacts, and is therefore advantageous in the evaluation of presurgical cases and in areas of the brain close to cavities in which the BOLD method cannot reliably be applied. J. Magn. Reson. Imaging 2008;28:1245–1250. © 2008 Wiley‐Liss, Inc.     

Quantifying the intra- and extravascular contributions to spin-echo fMRI at 3 T.

Functional MRI (fMRI) by means of spin-echo (SE) techniques provides an interesting alternative to gradient-echo methods because the contrast is based primarily on dynamic averaging associated with the blood oxygenation level-dependent (BOLD) effect. In this article the contributions from different brain compartments to BOLD signal changes in SE echo planar imaging (EPI) are investigated. To gain a better understanding of the underlying mechanisms that cause the fMRI contrast, two experiments are presented: First, the intravascular contribution is decomposed into two fractions with different regimes of flow by means of diffusion-weighting gradient schemes which are either flow-compensated, or will maximally dephase moving spins. Second, contributions from the intra- and extravascular space are selectively suppressed by combining flow-weighting with additional refocusing pulses. The results indicate two qualitatively different components of flowing blood which contribute to the BOLD contrast and a nearly equal share in functional signal from the intra- and extravascular compartments at TE approximately 80 ms and 3 T. Combining these results, there is evidence that at least one-half of the functional signal originates from the parenchyma in SE fMRI at 3 T. The authors suggest the use of flow-compensated diffusion weighting for SE fMRI to improve the sensitivity to the parenchyma.     

Three-dimensional spiral technique for high-resolution functional MRI.

For high-resolution functional MRI (fMRI) studies, signal-to-noise ratio (SNR) plays an important role. Any method that results in an improvement in SNR will be able to improve the quality of activation maps. Three-dimensional (3D) acquisition methods in general can provide higher SNR than that of 2D methods due to volume excitation. To demonstrate the superiority of 3D methods for high-resolution fMRI scans, a comparison study between 3D and 2D spiral methods was performed using a contrast-reversing checkerboard visual stimulus. A 3-inch surface coil was used to limit the in-plane FOV to 14 cm x 14 cm so that 32 1-mm slices with an in-plane voxel size of 1.1 mm x 1.1 mm could be acquired within 5.76 seconds. Results showed that average numbers of activated voxels were 407 and 841 for 2D and 3D methods, respectively (P < 0.01). Therefore, the 3D technique may be a useful alternative to the conventional 2D method for high resolution fMRI studies.     

语言血氧水平依赖功能MR扫描在神经外科导航手术中的应用

目的 利用经皮层电刺激的方法验证血氧水平依赖(BOLD)激活信号的准确性,并探讨语言BOLD技术在神经外科导航中的应用价值.方法 选取脑肿瘤患者8例,术前行BOLD-fMRI.然后清醒麻醉状态下唤醒患者,进行经皮层电刺激过程,在神经导航的指导下与BOLD信号进行点对点对照.将皮层电刺激阳性点与BOLD激活区位置比较,分别计算刺激阳性点位于BOLD激活区(真阳性)、非激活区(假阴性)的个数及刺激阴性点位于BOLD激活区(假阳性)、非激活区(真阴性)的个数,观察BOLD的敏感度和特异度.用两种不同的方法分别统计:即刺激阳性点位于BOLD激活区上和刺激阳性点距离BOLD激活区1 cm范围内.避开语言区1.0 cm外进行病灶切除,保留阳性点0.5～1.0 cm以内的皮质.结果 8例患者仅6例顺利完成任务.6例患者中,星形胶质细胞瘤Ⅱ级3例、Ⅲ级2例,胶母细胞瘤1例.共刺激48个点,其中阳性点11个.以刺激点位于BOLD激活区为标准,结果显示BOLD敏感度72.7%(8/11),特异度81.8%(30/37);以距离BOLD激活区小于1 cm为标准,BOLD敏感度82.0%(9/11),特异度75.6%(28/37).术后随访,患者均未出现失语表现.结论 语言BOLD激活区敏感度及特异度较高.但客观上因语言脑区个体变异较大,此项技术真正应用到临床有待于样本量增加和经验总结.

Abstract：

Objective To verify the accuracy of blood oxygenation level dependent (BOLD)-based activation using electrocortical stimulation mapping (ESM) and explore the value of language fMRI in the navigating operation of neurosurgery. Methods In 8 cases with brain tumors,BOLD-fMRI examinations were done before the operations. Under the state of awake anesthesia,the patients were aroused and ESM was conducted. Point-to-point comparison between the BOLD signal activations and the ESM was carried out under the surveillance of the neuro-navigation technology. In order to observe the sensibility and specificity of BOLD activations, the location of BOLD activations and the point of ESM was compared to calculate the stimulating positive points inside the regions of BOLD signals(real positive), outside BOLD regions(pseudo-negative), the stimulating negative points inside the regions of BOLD signals(pseudo-positive), and outside BOLD region(real negative). Two kinds of criteria for assessment were used. One was that the positive stimulating points were located in BOLD regions, and the other was that the positive stimulating points were located within 1 cm around the range of BOLD regions. Removal of the lesions were conducted with the tissue 1 cm around the language region preserved, and the cortex inside 0.5-1.0 cm distance from the positive points were retained. Results Of the 8 cases, only 6 finished the tasks. Among them, 3 cases were with astrocytoma of grade 2,2 were with astrocytoma of grade 3, and one with glioblastoma. The total number of stimulating points was 48, among which the positive points were 11. When the first criteria was applied, the sensitivity was 72.7% (8/11), and the specificity was 81.8% (30/37). When the second criteria was applied, the sensitivity was 82.0% (9/11),and the specificity was 75.6% (28/37). Follow-up after operation showed no aphasia occurred. Conclusions BOLD-fMRI had a high sensitivity and specificity in displaying the language regions. But due to the great variation of brain language area among the people, we need more studies of large sample to obtain enough experience before it can be used clinically.     

Spin-echo MRI underestimates functional changes in microvascular cerebral blood plasma volume using exogenous contrast agent.

While most functional MRI studies using exogenous contrast agent employ gradient-echo (GE) signal, spin echo (SE) imaging would represent an attractive alternative if its detection power were more comparable with GE imaging. This study demonstrates that SE methods systematically underestimate functional changes in microvascular cerebral blood plasma volume (CBV), so that SE detection power in brain tissue cannot match that provided by GE signal. Empirically, the in vivo response of SE-CBV was about 40% smaller than that of GE-CBV in rat brain at low basal values of CBV, a result that is consistent with physics predictions under the simplifying assumption of uniform vessel dilation. However, increasing values of basal CBV were associated with monotonically increasing mean vessel sizes and monotonically decreasing GE to SE ratios of functional changes in CBV (fCBV). This result suggests the presence of large but weakly reactive conduit vessels at high basal values of CBV. Hence, we conclude that GE imaging is the method of choice for functional MRI (fMRI) using exogenous contrast agent in most cases, although SE methods may represent a more spatially linear representation of underlying neural activity that becomes most apparent in regions with high basal CBV, such as the cortical surface.     

Resolution and reproducibility of BOLD and perfusion functional MRI at 3.0 Tesla.

Visual and somatosensory activation studies were performed on normal subjects to compare the spatial discrimination and reproducibility between functional MRI (fMRI) methods based on blood oxygen level-dependent (BOLD) and perfusion contrast. To allow simultaneous measurement of BOLD and perfusion contrast, a dedicated MRI acquisition technique was developed. Repeated experiments of sensory stimulation of single digits of the right hand showed an average variability of activation amplitude of 25% for BOLD data, and a significantly lower variability of 21% for perfusion data. No significant difference in the variability of the locus of activity was observed between the BOLD and perfusion data. In somatotopy experiments, digits II and V were subjected to passive sensory stimulation. Both the BOLD and perfusion data showed substantial overlap in the activation patterns from the two digits. In a retinotopy study, two stimuli were alternated to excite different patches of V1. Again there was substantial overlap between the activation patterns from both stimuli, although the perfusion performed somewhat better than the BOLD method. Particularly for the visual studies, the overlap in activation patterns was more than expected based on the fine-scale retinotopic mapping of cortical activity, suggesting that both BOLD and perfusion contrast mechanisms contribute substantially to the point-spread function (PSF).     

Blood oxygenation level-dependent (BOLD) MRI of human skeletal muscle at 1.5 and 3 T

Purpose:

To evaluate the dependence of skeletal muscle blood oxygenation level‐dependent (BOLD) effect and time course characteristics on magnetic field strength in healthy volunteers using an ischemia/reactive hyperemia paradigm.

Materials and Methods:

Two consecutive skeletal muscle BOLD magnetic resonance imaging (MRI) measurements in eight healthy volunteers were performed on 1.5 T and 3.0 T whole‐body MRI scanners. For both measurements a fat‐saturated multi‐shot multiecho gradient‐echo EPI sequence was applied. Temporary vascular occlusion was induced by suprasystolic cuff compression of the thigh. T2* time courses were obtained from two different calf muscles and characterized by typical curve parameters. Ischemia‐ and hyperemia‐induced changes in R2* (ΔR2*) were calculated for both muscles in each volunteer at the two field strengths.

Results:

Skeletal muscle BOLD changes are dependent on magnetic field strength as the ratio ΔR2*(3.0 T)/ΔR2*(1.5 T) was found to range between 1.6 and 2.2. Regarding time course characteristics, significantly higher relative T2* changes were found in both muscles at 3.0 T.

Conclusion:

The present study shows an approximately linear field strength dependence of ΔR2* in the skeletal muscle in response to ischemia and reactive hyperemia. Using higher magnetic fields is advisable for future BOLD imaging studies of peripheral limb pathologies. J. Magn. Reson. Imaging 2012;35:1227‐1232. © 2012 Wiley Periodicals, Inc.     

Comparison of the dependence of blood R2 and R2* on oxygen saturation at 1.5 and 4.7 Tesla.

Gradient-echo (GRE) blood oxygen level-dependent (BOLD) effects have both intra- and extravascular contributions. To better understand the intravascular contribution in quantitative terms, the spin-echo (SE) and GRE transverse relaxation rates, R(2) and R(2)(*), of isolated blood were measured as a function of oxygenation in a perfusion system. Over the normal oxygenation saturation range of blood between veins, capillaries, and arteries, the difference between these rates, R'(2) = R(2)(*) - R(2), ranged from 1.5 to 2.1 Hz at 1.5 T and from 26 to 36 Hz at 4.7 T. The blood data were used to calculate the expected intravascular BOLD effects for physiological oxygenation changes that are typical during visual activation. This modeling showed that intravascular DeltaR(2)(*) is caused mainly by R(2) relaxation changes, namely 85% and 78% at 1.5T and 4.7T, respectively. The simulations also show that at longer TEs (>70 ms), the intravascular contribution to the percentual BOLD change is smaller at high field than at low field, especially for GRE experiments. At shorter TE values, the opposite is the case. For pure parenchyma, the intravascular BOLD signal changes originate predominantly from venules for all TEs at low field and for short TEs at high field. At longer TEs at high field, the capillary contribution dominates. The possible influence of partial volume contributions with large vessels was also simulated, showing large (two- to threefold) increases in the total intravascular BOLD effect for both GRE and SE.     

Breathhold‐regulated blood oxygenation level‐dependent (BOLD) MRI of human brain at 3 tesla

Purpose:

To investigate the cerebrovascular response to repeated breathhold challenges using blood oxygenation level‐dependent (BOLD) MRI at 3T and compare the results with previous data at 1.5T.

Materials and Methods:

Six normal volunteers and six patients with brain tumors were recruited for this 3T study. For the normal group, BOLD MRI during repeated breathholds of different durations (five to 30 seconds) were acquired. Maximum signal change, full‐width at half‐maximum (FWHM) and onset time (defined as the time to the first half‐maximum) were determined by curve fitting. The fractional activation volume was also calculated. Patients performed a 10‐ or 15‐second breathhold paradigm according to individual capability.

Results:

Significant BOLD signal increases in the gray matter for a breathhold period as short as 5 seconds at 3T, instead of 10 seconds at 1.5T. The fractional activation volume vs. breathhold duration reached a plateau of 49.54 ± 7.26% at 15 seconds at 3T, which was higher and shorter than that at 1.5T. The maximum signal changes were significantly larger (a 69% increase) at 3T than at 1.5T. In the patient group, there were BOLD signal increases in gray matter but not in tumor bulk or perifocal edema, which agreed with the results previously found at 1.5T.

Conclusion:

BOLD MRI at 3T is more sensitive for detecting breathhold‐regulated signal changes than at 1.5T, which allows a shorter and more feasible breathhold paradigm for clinical applications in patients with brain tumors. J. Magn. Reson. Imaging 2010;31:78–84. © 2009 Wiley‐Liss, Inc.     

Repetition time in echo planar functional MRI.

To date, surprisingly little attention has been directed toward determining the optimum TR in a functional imaging experiment. A survey of the literature reveals a wide range of TRs, but little justification for a specific TR. Long-TR functional imaging experiments provide maximum signal-to-noise ratio (SNR) in the raw images; allow for the collection of a large number of slice locations; and decrease the size of the data set acquired, simplifying storage and handling. This work, however, demonstrates that long-TR imaging sacrifices statistical power when the paradigm timing is held fixed. That is, for a fixed-run duration consisting of multiple activation/control blocks, shorter TR acquisitions (on the order of 1000 ms) provide better discrimination between the activated and nonactivated brain tissue regions than do long-TR acquisitions (on the order of 4000 ms). Results are shown for modeling the functional imaging experiment and for three different paradigms performed on normal subjects.     

BOLD MRI of the human cervical spinal cord at 3 tesla.

The feasibility of functional MRI of the spinal cord was investigated by carrying out blood oxygen-level dependent (BOLD) imaging of the human cervical spinal cord at a field of 3 T. BOLD imaging of the cervical spinal cord showed an average intensity increase of 7.0% during repeated exercise with the dominant hand with a return to baseline during rest periods. The areas of activation were predominantly on the same side of the spinal cord as the hand performing the exercise, between the levels of the sixth cervical and first thoracic spinal cord segments. The direct correspondence between these areas and those involved with the transmission of motor impulses to the hand, and reception of sensory information from the hand, demonstrates that spinal functional magnetic resonance imaging is feasible. Magn Reson Med 42:571-576, 1999.