Robust imaging of hippocampal inner structure at 7T: in vivo acquisition protocol and methodological choices

Objective

Motion-robust multi-slab imaging of hippocampal inner structure in vivo at 7T.

Materials and methods

Motion is a crucial issue for ultra-high resolution imaging, such as can be achieved with 7T MRI. An acquisition protocol was designed for imaging hippocampal inner structure at 7T. It relies on a compromise between anatomical details visibility and robustness to motion. In order to reduce acquisition time and motion artifacts, the full slab covering the hippocampus was split into separate slabs with lower acquisition time. A robust registration approach was implemented to combine the acquired slabs within a final 3D-consistent high-resolution slab covering the whole hippocampus. Evaluation was performed on 50 subjects overall, made of three groups of subjects acquired using three acquisition settings; it focused on three issues: visibility of hippocampal inner structure, robustness to motion artifacts and registration procedure performance.

Results

Overall, T2-weighted acquisitions with interleaved slabs proved robust. Multi-slab registration yielded high quality datasets in 96 % of the subjects, thus compatible with further analyses of hippocampal inner structure.

Conclusion

Multi-slab acquisition and registration setting is efficient for reducing acquisition time and consequently motion artifacts for ultra-high resolution imaging of the inner structure of the hippocampus.

     

The traveling heads: multicenter brain imaging at 7 Tesla

Objective

This study evaluates the inter-site and intra-site reproducibility of 7 Tesla brain imaging and compares it to literature values for other field strengths.

Materials and methods

The same two subjects were imaged at eight different 7 T sites. MP2RAGE, TSE, TOF, SWI, EPI as well as B1 and B0 field maps were analyzed quantitatively to assess inter-site reproducibility. Intra-site reproducibility was measured with rescans at three sites.

Results

Quantitative measures of MP2RAGE scans showed high agreement. Inter-site and intra-site reproducibility errors were comparable to 1.5 and 3 T. Other sequences also showed high reproducibility between the sites, but differences were also revealed. The different RF coils used were the main source for systematic differences between the sites.

Conclusion

Our results show for the first time that multi-center brain imaging studies of the supratentorial brain can be performed at 7 T with high reproducibility and similar reliability as at 3T. This study develops the basis for future large-scale 7 T multi-site studies.

     

Subjective perception of safety in healthy individuals working with 7 T MRI scanners: a retrospective multicenter survey

Objective

To retrospectively assess perception of safety of healthy individuals working with human 7 Tesla (T) magnetic resonance imaging (MRI) scanners.

Materials and methods

A total of 66 healthy individuals with a mean age of 31 ± 7 years participated in this retrospective multicentre survey study. Nonparametric correlation analysis was conducted to evaluate the relation between self-reported perception of safety and prevalence of sensory effects while working with 7 T MRI scanners for an average 47 months.

Results

The results indicated that 98.5 % of the study participants had a neutral or positive feeling about safety aspects at 7 T MRI scanners. 45.5 % reported that they feel very safe and none of the participants stated that they feel moderately or very unsafe while working with 7 T MRI scanners. Perception of safety was not affected by the number of hours per week spent in the vicinity of the 7 T MRI scanner or the duration of experience with 7 T MRI. More than 50 % of individuals experienced vertigo and metallic taste while working with 7 T MRI scanners. However, participants’ perceptions of safety were not affected by the prevalence of MR-related symptoms.

Conclusions

The overall data indicated an average perception of a moderately safe work environment. To our knowledge, this study delineates the first attempt to assess the subjective safety perception among 7 T MRI workers and suggests further investigations are indicated.

     

Theory of MRI contrast in the annulus fibrosus of the intervertebral disc

Objective

Here we develop a three-dimensional analytic model for MR image contrast of collagen lamellae in the annulus fibrosus of the intervertebral disc of the spine, based on the dependence of the MRI signal on collagen fiber orientation.

Materials and methods

High-resolution MRI scans were performed at 1.5 and 7 T on intact whole disc specimens from ovine, bovine, and human spines. An analytic model that approximates the three-dimensional curvature of the disc lamellae was developed to explain inter-lamellar contrast and intensity variations in the annulus. The model is based on the known anisotropic dipolar relaxation of water in tissues with ordered collagen.

Results

Simulated MRI data were generated that reproduced many features of the actual MRI data. The calculated inter-lamellar image contrast demonstrated a strong dependence on the collagen fiber angle and on the circumferential location within the annulus.

Conclusion

This analytic model may be useful for interpreting MR images of the disc and for predicting experimental conditions that will optimize MR image contrast in the annulus fibrosus.

     

Automated reference-free detection of motion artifacts in magnetic resonance images

Objectives

Our objectives were to provide an automated method for spatially resolved detection and quantification of motion artifacts in MR images of the head and abdomen as well as a quality control of the trained architecture.

Materials and methods

T1-weighted MR images of the head and the upper abdomen were acquired in 16 healthy volunteers under rest and under motion. Images were divided into overlapping patches of different sizes achieving spatial separation. Using these patches as input data, a convolutional neural network (CNN) was trained to derive probability maps for the presence of motion artifacts. A deep visualization offers a human-interpretable quality control of the trained CNN. Results were visually assessed on probability maps and as classification accuracy on a per-patch, per-slice and per-volunteer basis.

Results

On visual assessment, a clear difference of probability maps was observed between data sets with and without motion. The overall accuracy of motion detection on a per-patch/per-volunteer basis reached 97%/100% in the head and 75%/100% in the abdomen, respectively.

Conclusion

Automated detection of motion artifacts in MRI is feasible with good accuracy in the head and abdomen. The proposed method provides quantification and localization of artifacts as well as a visualization of the learned content. It may be extended to other anatomic areas and used for quality assurance of MR images.

     

3D <Emphasis Type="Italic">T</Emphasis><Subscript>2</Subscript>-weighted imaging at 7T using dynamic k<Subscript>T</Subscript>-points on single-transmit MRI systems

Objectives

For turbo spin echo (TSE) sequences to be useful at ultra-high field, they should ideally employ an RF pulse train compensated for the B ₁ ⁺ inhomogeneity. Previously, it was shown that a single k_T-point pulse designed in the small tip-angle regime can replace all the pulses of the sequence (static k_T-points). This work demonstrates that the B ₁ ⁺ dependence of T ₂-weighted imaging can be further mitigated by designing a specific k_T-point pulse for each pulse of a 3D TSE sequence (dynamic k_T-points) even on single-channel transmit systems

Materials and methods

By combining the spatially resolved extended phase graph formalism (which calculates the echo signals throughout the sequence) with a gradient descent algorithm, dynamic k_T-points were optimized such that the difference between the simulated signal and a target was minimized at each echo. Dynamic k_T-points were inserted into the TSE sequence to acquire in vivo images at 7T.

Results

The improvement provided by the dynamic k_T-points over the static k_T-point design and conventional hard pulses was demonstrated via simulations. Images acquired with dynamic k_T-points showed systematic improvement of signal and contrast at 7T over regular TSE—especially in cerebellar and temporal lobe regions without the need of parallel transmission.

Conclusion

Designing dynamic k_T-points for a 3D TSE sequence allows the acquisition of T ₂-weighted brain images on a single-transmit system at ultra-high field with reduced dropout and only mild residual effects due to the B ₁ ⁺ inhomogeneity.

     

Ultrashort echo time and zero echo time MRI at 7T

Objective

Zero echo time (ZTE) and ultrashort echo time (UTE) pulse sequences for MRI offer unique advantages of being able to detect signal from rapidly decaying short-T2 tissue components. In this paper, we applied 3D ZTE and UTE pulse sequences at 7T to assess differences between these methods.

Materials and methods

We matched the ZTE and UTE pulse sequences closely in terms of readout trajectories and image contrast. Our ZTE used the water- and fat-suppressed solid-state proton projection imaging method to fill the center of k-space. Images from healthy volunteers obtained at 7T were compared qualitatively, as well as with SNR and CNR measurements for various ultrashort, short, and long-T2 tissues.

Results

We measured nearly identical contrast-to-noise and signal-to-noise ratios (CNR/SNR) in similar scan times between the two approaches for ultrashort, short, and long-T2 components in the brain, knee and ankle. In our protocol, we observed gradient fidelity artifacts in UTE, and our chosen flip angle and readout also resulted in shading artifacts in ZTE due to inadvertent spatial selectivity. These can be corrected by advanced reconstruction methods or with different chosen protocol parameters.

Conclusion

The applied ZTE and UTE pulse sequences achieved similar contrast and SNR efficiency for volumetric imaging of ultrashort-T2 components. Key differences include that ZTE is limited to volumetric imaging, but has substantially reduced acoustic noise levels during the scan. Meanwhile, UTE has higher acoustic noise levels and greater sensitivity to gradient fidelity, but offers more flexibility in image contrast and volume selection.

     

Neuromyelitis optica does not impact periventricular venous density versus healthy controls: a 7.0 Tesla MRI clinical study

Objective

To quantify the periventricular venous density in neuromyelitis optica spectrum disease (NMOSD) in comparison to that in patients with multiple sclerosis (MS) and healthy control subjects.

Materials and methods

Sixteen patients with NMOSD, 16 patients with MS and 16 healthy control subjects underwent 7.0-Tesla (7T) MRI. The imaging protocol included T₂*-weighted (T₂*w) fast low angle-shot (FLASH) and fluid-attenuated inversion recovery (FLAIR) sequences. The periventricular venous area (PVA) was manually determined by a blinded investigator in order to estimate the periventricular venous density in a region of interest-based approach.

Results

No significant differences in periventricular venous density indicated by PVA were detectable in NMOSD versus healthy controls (p = 0.226). In contrast, PVA was significantly reduced in MS patients compared to healthy controls (p = 0.013).

Conclusion

Unlike patients with MS, those suffering from NMOSD did not show reduced venous visibility. This finding may underscore primary and secondary pathophysiological differences between these two distinct diseases of the central nervous system.

     

Application of the limited-memory quasi-Newton algorithm for multi-dimensional,large flip-angle RF pulses at 7T

Objective

Ultrahigh field MRI provides great opportunities for medical diagnostics and research. However, ultrahigh field MRI also brings challenges, such as larger magnetic susceptibility induced field changes. Parallel-transmit radio-frequency pulses can ameliorate these complications while performing advanced tasks in routine applications. To address one class of such pulses, we propose an optimal-control algorithm as a tool for designing advanced multi-dimensional, large flip-angle, radio-frequency pulses. We contrast initial conditions, constraints, and field correction abilities against increasing pulse trajectory acceleration factors.

Materials and methods

On an 8-channel 7T system, we demonstrate the quasi-Newton algorithm with pulse designs for reduced field-of-view imaging with an oil phantom and in vivo with scans of the human brain stem. We used echo-planar imaging with 2D spatial-selective pulses. Pulses are computed sufficiently rapid for routine applications.

Results

Our dataset was quantitatively analyzed with the conventional mean-square-error metric and the structural-similarity index from image processing. Analysis of both full and reduced field-of-view scans benefit from utilizing both complementary measures.

Conclusion

We obtained excellent outer-volume suppression with our proposed method, thus enabling reduced field-of-view imaging using pulse trajectory acceleration factors up to 4.

     

A novel MR-compatible sensor to assess active medical device safety: stimulation monitoring,rectified radio frequency pulses,and gradient-induced voltage measurements

Purpose

To evaluate the function of an active implantable medical device (AIMD) during magnetic resonance imaging (MRI) scans. The induced voltages caused by the switching of magnetic field gradients and rectified radio frequency (RF) pulse were measured, along with the AIMD stimulations.

Materials and methods

An MRI-compatible voltage probe with a bandwidth of 0–40 kHz was designed. Measurements were carried out both on the bench with an overvoltage protection circuit commonly used for AIMD and with a pacemaker during MRI scans on a 1.5 T (64 MHz) MR scanner.

Results

The sensor exhibits a measurement range of?±?15 V with an amplitude resolution of 7 mV and a temporal resolution of 10 µs. Rectification was measured on the bench with the overvoltage protection circuit. Linear proportionality was confirmed between the induced voltage and the magnetic field gradient slew rate. The pacemaker pacing was recorded successfully during MRI scans.

Conclusion

The characteristics of this low-frequency voltage probe allow its use with extreme RF transmission power and magnetic field gradient positioning for MR safety test of AIMD during MRI scans.

     

Can MRI T<Subscript>1</Subscript> be used to detect early changes in 5xFAD Alzheimer’s mouse brain?

Objectives

In the present study, we have tested whether MRI T₁ relaxation time is a sensitive marker to detect early stages of amyloidosis and gliosis in the young 5xFAD transgenic mouse, a well-established animal model for Alzheimer’s disease.

Materials and methods

5xFAD and wild-type mice were imaged in a 4.7 T Varian horizontal bore MRI system to generate T₁ quantitative maps using the spin-echo multi-slice sequence. Following immunostaining for glial fibrillary acidic protein, Iba-1, and amyloid-β, T₁ and area fraction of staining were quantified in the posterior parietal and primary somatosensory cortex and corpus callosum.

Results

In comparison with age-matched wild-type mice, we observed first signs of amyloidosis in 2.5-month-old 5xFAD mice, and development of gliosis in 5-month-old 5xFAD mice. In contrast, MRI T₁ relaxation times of young, i.e., 2.5- and 5-month-old, 5xFAD mice were not significantly different to those of age-matched wild-type controls. Furthermore, although disease progression was detectable by increased amyloid-β load in the brain of 5-month-old 5xFAD mice compared with 2.5-month-old 5xFAD mice, MRI T₁ relaxation time did not change.

Conclusions

In summary, our data suggest that MRI T₁ relaxation time is neither a sensitive measure of disease onset nor progression at early stages in the 5xFAD mouse transgenic mouse model.

     

Non-gadolinium dynamic angiography of the neurovasculature using arterial spin labeling MRI: preliminary experience in children

Objective

We demonstrate the potential clinical utility of a 4D non-gadolinium dynamic angiography technique based on arterial spin-labeling called contrast inherent inflow enhanced multi-phase angiography (CINEMA) in pediatric patients.

Materials and Methods

CINEMA was qualitatively compared to conventional time-of-flight (TOF) angiography in a cohort of 31 pediatric patients at 3 Tesla.

Results

CINEMA data were successfully acquired and reconstructed in all patients with no image artifacts. There were no cases where CINEMA was rated inferior to TOF in depicting intracranial vessel conspicuity. In 19 cases, CINEMA was rated equivalent to TOF and in the 12 remaining cases CINEMA was rated superior to TOF.

Conclusion

There is a steadily rising concern in adults and children over the potential effects of intracranial deposition of gadolinium. CINEMA is therefore a viable alternative in dynamic neurovascular imaging.

     

Motion-compensated data decomposition algorithm to accelerate dynamic cardiac MRI

Objectives

In dynamic cardiac magnetic resonance imaging (MRI), the spatiotemporal resolution is often limited by low imaging speed. Compressed sensing (CS) theory can be applied to improve imaging speed and spatiotemporal resolution. The combination of compressed sensing and low-rank matrix completion represents an attractive means to further increase imaging speed. By extending prior work, a Motion-Compensated Data Decomposition (MCDD) algorithm is proposed to improve the performance of CS for accelerated dynamic cardiac MRI.

Materials and methods

The process of MCDD can be described as follows: first, we decompose the dynamic images into a low-rank (L) and a sparse component (S). The L component includes periodic motion in the background, since it is highly correlated among frames, and the S component corresponds to respiratory motion. A motion-estimation/motion-compensation (ME-MC) algorithm is then applied to the low-rank component to reconstruct a cardiac motion compensated dynamic cardiac MRI.

Results

With validations on the numerical phantom and in vivo cardiac MRI data, we demonstrate the utility of the proposed scheme in significantly improving compressed sensing reconstructions by minimizing motion artifacts. The proposed method achieves higher PSNR and lower MSE and HFEN for medium to high acceleration factors.

Conclusion

The proposed method is observed to yield reconstructions with minimal spatiotemporal blurring and motion artifacts in comparison to the existing state-of-the-art methods.

     

Quantitative pulsed CEST-MRI at a clinical 3T MRI system

Objectives

The goal of this study was to quantify CEST related parameters such as chemical exchange rate and fractional concentration of exchanging protons at a clinical 3T scanner. For this purpose, two CEST quantification approaches—the AREX metric (for ‘apparent exchange dependent relaxation’), and the AREX-based Ω-plot method were used. In addition, two different pulsed RF irradiation schemes, using Gaussian-shaped and spin-lock pulses, were compared.

Materials and methods

Numerical simulations as well as MRI measurements in phantoms were performed. For simulations, the Bloch–McConnell equations were solved using a two-pool exchange model. MR experiments were performed on a clinical 3T MRI scanner using a cylindrical phantom filled with creatine solution at different pH values and different concentrations.

Results

The validity of the Ω-plot method and the AREX approach using spin-lock preparation for determination of the quantitative CEST parameters was demonstrated. Especially promising results were achieved for the Ω-plot method when the spin-lock preparation was employed.

Conclusion

Pulsed CEST at 3T could be used to quantify parameters such as exchange rate constants and concentrations of protons exchanging with free water. In the future this technique might be used to estimate the exchange rates and concentrations of biochemical substances in human tissues in vivo.

     

7 Tesla quantitative hip MRI: a comparison between TESS and CPMG for T2 mapping

Objectives

We aimed to evaluate the feasibility of triple-echo steady state (TESS) T2 mapping as an alternative to conventional multi-echo-spin-echo (CPMG) T2 mapping for the quantitative assessment of hip joint cartilage at 7 T.

Materials and methods

A total of eight healthy volunteers and three patients were included. Reproducibility of both techniques was evaluated in five volunteers in five scans each. T2 relaxation times were measured by manually drawing regions of interest in multiple regions of the hip joint. Data from both methods were compared using Pearson correlation coefficient, intra-class correlation coefficient, and coefficient of repeatability. The overall image quality and presence of artifacts was assessed.

Results

Cartilage transplant and surrounding fluid were well depicted by both methods. Compared to CPMG, TESS provided systematically reduced T2 values (43.3 ± 7.3 vs. 19.2 ± 5.5 ms for acetabular cartilage, and 41.4 ± 5.6 vs. 21.7 ± 5.2 ms for femoral cartilage), in line with previously reported values. No correlation between both methods was found. TESS yielded a slightly better reproducibility than CPMG, while CPMG showed pronounced sensitivity to B1 inhomogeneities.

Conclusion

TESS seems to be an attractive alternative to CPMG for improvements in quantitative hip joint imaging at 7 T, allowing shortening of the total acquisition time paired with insensitivity to B1, while rendering comparable image quality with good repeatability.

     

Reproducibility of locus coeruleus and substantia nigra imaging with neuromelanin sensitive MRI

Objectives

The purpose of this study was to assess the reproducibility of substantia nigra pars compacta (SNpc) and locus coeruleus (LC) delineation and measurement with neuromelanin-sensitive MRI.

Materials and methods

Eleven subjects underwent two neuromelanin-sensitive MRI scans. SNpc and LC volumes were extracted for each scan. Reproducibility of volume and magnetization transfer contrast measurements in SNpc and LC was assessed using intraclass correlation coefficients (ICC) and dice similarity coefficients (DSC).

Results

SNpc and LC volume measurements showed excellent reproducibility (SNpc-ICC: 0.94, p < 0.001; LC-ICC: 0.96, p < 0.001). SNpc and LC were accurately delineated between scans (SNpc-DSC: 0.80 ± 0.03; LC-DSC: 0.63 ± 0.07).

Conclusion

Neuromelanin-sensitive MRI can consistently delineate SNpc and LC.

     

Magnetic resonance imaging detection of multiple ischemic injury produced in an adult rat model of minor stroke followed by mild transient cerebral ischemia

Objectives

To determine whether cumulative brain damage produced adjacent to a minor stroke that is followed by a mild transient ischemia is detectable with MRI and histology, and whether acute or chronic recovery between insults influences this damage.

Materials and methods

A minor photothrombotic (PT) stroke was followed acutely (1–2 days) or chronically (7 days) by a mild transient middle cerebral artery occlusion (tMCAO). MRI was performed after each insult, followed by final histology.

Results

The initial PT produced small hyperintense T₂ and DW infarct lesions and peri-lesion regions of scattered necrosis and modestly increased T₂. Following tMCAO, in a slice and a region adjacent to the PT, a region of T₂ augmentation was observed when recovery between insults was acute but not chronic. Within the PT slice, a modest region of exacerbated T₂ change proximate to the PT was also observed in the chronic group. Corresponding histological changes within regions of augmented T₂ included increased vacuolation and cell death.

Conclusion

Within regions adjacent to an experimental minor stroke, a recurrence of a mild transient cerebral ischemia augmented T₂ above increases produced by tMCAO alone, reflecting increased damage in this region. Exacerbation appeared broader with acute versus chronic recovery between insults.

     

Volumetric imaging with homogenised excitation and static field at 9.4 T

Objectives

To overcome the challenges of B₀ and RF excitation inhomogeneity at ultra-high field MRI, a workflow for volumetric B₀ and flip-angle homogenisation was implemented on a human 9.4 T scanner.

Materials and methods

Imaging was performed with a 9.4 T human MR scanner (Siemens Medical Solutions, Erlangen, Germany) using a 16-channel parallel transmission system. B₀- and B₁-mapping were done using a dual-echo GRE and transmit phase-encoded DREAM, respectively. B₀ shims and a small-tip-angle-approximation kT-points pulse were calculated with an off-line routine and applied to acquire T₁- and T ₂ ^* -weighted images with MPRAGE and 3D EPI, respectively.

Results

Over six in vivo acquisitions, the B₀-distribution in a region-of-interest defined by a brain mask was reduced down to a full-width-half-maximum of 0.10 ± 0.01 ppm (39 ± 2 Hz). Utilising the kT-points pulses, the normalised RMSE of the excitation was decreased from CP-mode’s 30.5 ± 0.9 to 9.2 ± 0.7 % with all B ₁ ⁺  voids eliminated. The SNR inhomogeneities and contrast variations in the T₁- and T ₂ ^* -weighted volumetric images were greatly reduced which led to successful tissue segmentation of the T₁-weighted image.

Conclusion

A 15-minute B₀- and flip-angle homogenisation workflow, including the B₀- and B₁-map acquisitions, was successfully implemented and enabled us to reduce intensity and contrast variations as well as echo-planar image distortions in 9.4 T images.

     

Acoustic noise reduction in <Emphasis Type="Italic">T</Emphasis><Subscript>1</Subscript>- and proton-density-weighted turbo spin-echo imaging

Objective

To reduce acoustic noise levels in T ₁-weighted and proton-density-weighted turbo spin-echo (TSE) sequences, which typically reach acoustic noise levels up to 100 dB(A) in clinical practice.

Materials and methods

Five acoustic noise reduction strategies were combined: (1) gradient ramps and shapes were changed from trapezoidal to triangular, (2) variable-encoding-time imaging was implemented to relax the phase-encoding gradient timing, (3) RF pulses were adapted to avoid the need for reversing the polarity of the slice-rewinding gradient, (4) readout bandwidth was increased to provide more time for gradient activity on other axes, (5) the number of slices per TR was reduced to limit the total gradient activity per unit time. We evaluated the influence of each measure on the acoustic noise level, and conducted in vivo measurements on a healthy volunteer. Sound recordings were taken for comparison.

Results

An overall acoustic noise reduction of up to 16.8 dB(A) was obtained by the proposed strategies (1–4) and the acquisition of half the number of slices per TR only. Image quality in terms of SNR and CNR was found to be preserved.

Conclusions

The proposed measures in this study allowed a threefold reduction in the acoustic perception of T ₁-weighted and proton-density-weighted TSE sequences compared to a standard TSE-acquisition. This could be achieved without visible degradation of image quality, showing the potential to improve patient comfort and scan acceptability.

     

Automatic labeling of cerebral arteries in magnetic resonance angiography

Objectives

In order to introduce 4D flow magnetic resonance imaging (MRI) as a standard clinical instrument for studying the cerebrovascular system, new and faster postprocessing tools are necessary. The objective of this study was to construct and evaluate a method for automatic identification of individual cerebral arteries in a 4D flow MRI angiogram.

Materials and methods

Forty-six elderly individuals were investigated with 4D flow MRI. Fourteen main cerebral arteries were manually labeled and used to create a probabilistic atlas. An automatic atlas-based artery identification method (AAIM) was developed based on vascular-branch extraction and the atlas was used for identification. The method was evaluated by comparing automatic with manual identification in 4D flow MRI angiograms from 67 additional elderly individuals.

Results

Overall accuracy was 93 %, and internal carotid artery and middle cerebral artery labeling was 100 % accurate. Smaller and more distal arteries had lower accuracy; for posterior communicating arteries and vertebral arteries, accuracy was 70 and 89 %, respectively.

Conclusion

The AAIM enabled fast and fully automatic labeling of the main cerebral arteries. AAIM functionality provides the basis for creating an automatic and powerful method to analyze arterial cerebral blood flow in clinical routine.