Josef Pfeuffer

Sustained negative BOLD, blood flow and oxygen consumption response and its coupling to the positive response in the human brain

Most fMRI studies are based on the detection of a positive BOLD response (PBR). Here, we demonstrate and characterize a robust sustained negative BOLD response (NBR) in the human occipital cortex, triggered by stimulating part of the visual field. The NBR was spatially adjacent to but segregated from the PBR. It depended on the stimulus and thus on the pattern of neuronal activity. The time courses of the NBR and PBR were similar, and their amplitudes covaried both with increasing stimulus duration and increasing stimulus contrast. The NBR was associated with reductions in blood flow and with decreases in oxygen consumption. Our findings support the contribution to the NBR of (1) a significant component of reduction in neuronal activity and (2) possibly a component of hemodynamic changes independent of the local changes in neuronal activity.

Imaging brain function in humans at 7 Tesla.

This article describes experimental studies performed to demonstrate the feasibility of BOLD fMRI using echo‐planar imaging (EPI) at 7 T and to characterize the BOLD response in humans at this ultrahigh magnetic field. Visual stimulation studies were performed in normal subjects using high‐resolution multishot EPI sequences. Changes in R  *2 arising from visual stimulation were experimentally determined using fMRI measurements obtained at multiple echo times. The results obtained at 7 T were compared to those at 4 T. Experimental data indicate that fMRI can be reliably performed at 7 T and that at this field strength both the sensitivity and spatial specificity of the BOLD response are increased. This study suggests that ultrahigh field MR systems are advantageous for functional mapping in humans. Magn Reson Med 45:588–594, 2001.

Correction of physiologically induced global off‐resonance effects in dynamic echo‐planar and spiral functional imaging

In functional magnetic resonance imaging, a rapid method such as echo‐planar (EPI) or spiral is used to collect a dynamic series of images. These techniques are sensitive to changes in resonance frequency which can arise from respiration and are more significant at high magnetic fields. To decrease the noise from respiration‐induced phase and frequency fluctuations, a simple correction of the “dynamic off‐resonance in k‐space” (DORK) was developed. The correction uses phase information from the center of k‐space and a navigator echo and is illustrated with dynamic scans of single‐shot and segmented EPI and, for the first time, spiral imaging of the human brain at 7 T. Image noise in the respiratory spectrum was measured with an edge operator. The DORK correction significantly reduced respiration‐induced noise (image shift for EPI, blurring for spiral, ghosting for segmented acquisition). While spiral imaging was found to exhibit less noise than EPI before correction, the residual noise after the DORK correction was comparable. The correction is simple to apply and can correct for other sources of frequency drift and fluctuations in dynamic imaging. Magn Reson Med 47:344–353, 2002.

Respiration-induced B0 fluctuations and their spatial distribution in the human brain at 7 Tesla.

In functional magnetic resonance imaging (fMRI), it is known that physiological influences such as cardiac pulsation, respiration, and brain motion can induce fluctuations in signal intensity and phase. Some of the mechanisms potentially involved in those phenomena are expected to be amplified at higher magnetic fields. This study addresses the issue of B0 fluctuations induced by susceptibility changes during respiration attributed to movements of chest and diaphragm, and variations in the oxygen concentration. It is demonstrated that respiration‐induced resonance offsets (RIROs) are significant at 7T. Data were acquired with an RF pulse (no gradients), multislice echo‐planar imaging (EPI), and dynamic 3D fast low‐angle shot (3D‐ FLASH) imaging. Three main observations summarize the experimental findings. First, in FIDs measured after a single RF pulse, a RIRO with a large amplitude was consistently detected, although the average amplitude varied between subjects from 1.45 Hz to 4 Hz. Second, in transverse EPI images obtained in the occipital lobe, the RIRO amplitude showed a monotonic increase along the z axis toward the lungs. Third, a more detailed spatial analysis with 3D‐FLASH phase maps revealed that a previously published analytical model can accurately describe the spatial distribution of RIRO. Consequential apparent motions in the EPI series, as well as the implications of slice orientation for correction strategies are discussed. Magn Reson Med 47:888–895, 2002.

Restricted diffusion and exchange of intracellular water: theoretical modelling and diffusion time dependence of 1H NMR measurements on perfused glial cells

Intracellular diffusion properties of water in F98 glioma cells immobilized in basement membrane gel threads, are investigated with a pulsed‐field‐gradient spin‐echo NMR technique at diffusion times from 6 to 2000 ms and at different temperatures. In extended model calculations the concept of ‘restricted intracellular diffusion at permeable boundaries’ is described by a combined Tanner–Kärger formula. Signal components in a series of ct experiments (constant diffusion time) are separated due to different diffusion properties (Gaussian and restricted diffusion), and physiological as well as morphological cell parameters are extracted from the experimental data. The intracellular apparent diffusion coefficients strongly depend on the diffusion time and are up to two orders of magnitude smaller than the self diffusion constant of water. Propagation lengths are found to be in the range of 4–7 μm. Hereby intracellular signals of compartments with a characteristic diameter could be selected by an appropriate gradient strength. With cg experiments (constant gradient) a mean intracellular residence time for water is determined to be about 50 ms, and the intrinsic intracellular diffusion constant is estimated to 1 × 10−3  mm2 /s. Studying the water diffusion in glial cells provides basic understanding of the intracellular situation in brain tissue and may elucidate possible influences on the changes in the diffusion contrast during ischemic conditions.

Extracellular-intracellular distribution of glucose and lactate in the rat brain assessed noninvasively by diffusion-weighted 1H nuclear magnetic resonance spectroscopy in vivo

To determine the distribution of cerebral glucose and lactate between the intracellular and the extracellular space of the rat brain in vivo, the diffusion characteristic of glucose and lactate was compared with that of metabolites known to be mainly intracellular (N-acetylaspartate, choline, creatine, glutamate, myo-inositol, and taurine) using a pulsed-field-gradient 1H nuclear magnetic resonance technique. The detection of a glucose signal at large diffusion weighting provided direct experimental evidence of intracellular glucose in the rat brain. At large diffusion weighting, the apparent diffusion coefficient (ADC) of glucose and lactate was similar to that of the intracellular metabolites such as N-acetylaspartate, creatine, and glutamate. At small diffusion weighting, the ADC of glucose and lactate was increased, which was explained by a decreased relative contribution of intracellular glucose to the total signal. The calculated extracellular volume fraction of glucose (0.19 ± 0.05) and lactate (0.17 ± 0.06) was consistent with a substantial fraction of glucose and lactate signals being intracellular. The findings were direct in vivo evidence that the largest concentration gradient of glucose is at the blood-brain barrier and that glucose is evenly distributed in the brain in vivo between the intracellular and extracellular space.

Zoomed Functional Imaging in the Human Brain at 7 Tesla with Simultaneous High Spatial and High Temporal Resolution

Functional neuroimaging in the human brain using noninvasive magnetic resonance methods has the potential of providing highly resolved maps of neuronal activation. Decreasing the voxel size and obtaining simultaneously high temporal resolution is a major challenge and is mainly limited by sensitivity. Here, signal-to-noise gains at high magnetic fields (7 Tesla) and an optimized surface coil setup are combined with a novel approach for zoomed functional imaging in the visual cortex. For echoplanar imaging, the acquisition time and segmentation was shortened fourfold by using a reduced field-of-view. An adiabatic outer-volume suppression method, BISTRO, was used to obliterate signal outside the area-of-interest achieving effective suppression even for inhomogeneous B1-fields. A single-shot acquisition was performed at submillimeter resolution in the human brain, while simultaneously maintaining a high temporal resolution of 125 ms. Functional studies with and without field-of-view reduction were performed. Activation and percent change maps were compared with respect to spatial extent, t values and percentage changes of the BOLD contrast. The detection of functional activation was found to be equal within the inter-series variability for the two acquisition schemes. Thus, single-trial BOLD responses were detected for the first time robustly at a 500 x 500 microm2 in plane and 250 ms temporal resolution, significantly expanding the possibilities of event-related functional imaging in the human brain. The magnetization transfer effect induced by the outer-volume suppression pulses was investigated and found to be increased during neuronal activity.

Perfusion-based high-resolution functional imaging in the human brain at 7 Tesla

Perfusion‐based MRI measures cerebral blood flow (CBF) at the capillary level and can be used for functional studies based on the tight spatial coupling between brain activity and blood flow. Obtaining functional CBF maps with high spatial resolution is a major challenge because the CBF signal is intrinsically low and the SNR is critical. In the present work, CBF‐based functional imaging was performed at a considerably smaller voxel size than previously reported in humans. High‐resolution CBF maps were obtained with voxel sizes as small as 0.9 × 0.9 × 1.5 mm3 in the human brain. High sensitivity was made possible by signal‐to‐noise gains at the high magnetic field of 7 T and by using a novel RF combination coil design. In addition, a reduction of the field‐of‐view was critical to achieve 0.9‐mm in‐plane resolution with gradient‐echo echo‐planar imaging in a single shot. Functional CBF data were compared with functional BOLD data to reveal that, for CBF, large contrast‐ to‐noise gains were obtained at high spatial resolution, indicating that the functional CBF response was more localized. High‐resolution functional CBF imaging is significant for neuroscience research because it provides better localization and more specific information than BOLD for monitoring brain function. Magn Reson Med 47:903–911, 2002.

Regional Reproducibility of Pulsed Arterial Spin Labeling Perfusion Imaging at 3T

Arterial spin labeling (ASL) is a promising non-invasive magnetic resonance imaging (MRI) technique for measuring regional cerebral blood flow (rCBF) or perfusion in vivo. To evaluate the feasibility of ASL as a biomarker for clinical trials, it is important to examine test-retest reproducibility. We investigated both inter- and intra-session reproducibility of perfusion MRI using a pulsed ASL (PASL) sequence PICORE Q2TIPS with an echo-planar imaging (EPI) readout. Structural MRI regions of interest (ROIs) were extracted individually by automated parcellation and segmentation methods using FreeSurfer. These cortical and subcortical ROIs were used to assess regional perfusion stability. Our results indicated regional variability in grey matter rCBF. Although rCBF measurements were characterized by intersubject variation, our results also indicated relatively less within-subject variability estimated as within-subject standard deviation (SD(W)) (intersession SD(W): 2.0 to 8.8; intrasession SD(W): 2.8 to 9.6) and acceptable reliabilities as measured using intraclass correlation coefficient (ICC) (intersession ICC: 0.68 to 0.94; intrasession ICC: 0.66 to 0.95) for regional MRI perfusion measurements using the PICORE Q2TIPS technique. Overall, our findings suggest that PASL is a technique with good within and between session reproducibility. Further reproducibility studies in target populations relevant for specific clinical trials of neurovascular related agents will be important and the present results provide a framework for such assessments.

Monitoring of cell volume and water exchange time in perfused cells by diffusion‐weighted 1H NMR spectroscopy

Diffusion of intracellular water was measured in perfused cells embedded in basement membrane gel threads. F98 glioma cells, primary astrocytes, and epithelial KB cells were used and were exposed to osmotic stress, immunosuppressiva, the water channel blocker p ‐chloromercuriobenzenesulfonate (p CMBS), and apoptotic conditions. With diffusion‐weighted 1 H NMR spectroscopy changes in the intracellular signal could be monitored and quantified with single signal (ss ), constant diffusion time (ct ), and constant gradient strength (cg ) experiments. The temporal resolution of the ss monitoring was 3.5 s with a standard deviation of 0.5% of the signal intensity and 32 s (3%) with ct monitoring, respectively. A mean intracellular residence time of water was determined with the cg experiment to about 50 ms. Changes of this exchange time from (51.9 ± 1.0) to (59.0 ± 1.1) ms were observed during treatment with p CMBS. The changes in the diffusion attenuated signal could be simulated analytically varying the intracellular volume fraction and exchange time by combination of restricted diffusion (Tanner model) and water exchange (Kärger model). This sensitive and noninvasive NMR method on perfused cells allows to determine changes in the intracellular volume and residence time in a simple and accurate manner. Many further applications as anoxia, volume regulation, ischemia and treatment with various pharmaceuticals are conceiveable to follow up their effect on the cell volume and the exchange time of intracellular water.