J.A. Frank

Functional Mapping of Human Sensorimotor Cortex with 3D BOLD fMRI Correlates Highly With H215O PET rCBF

Positron emission tomography (PET) functional imaging is based on changes in regional cerebral blood flow (rCBF). Functional magnetic resonance imaging (fMRI) is based on a variety of physiological parameters as well as rCBF. This study is aimed at the cross validation of three-dimensional (3D) fMRI, which is sensitive to changes in blood oxygenation, with oxygen-15-labeled water (H215O) PET. Nine normal subjects repeatedly performed a simple finger opposition task during fMRI scans and during PET scans. Within-subject statistical analysis revealed significant (“activated”) signal changes (p < 0.05, Bonferroni corrected for number of voxels) in contralateral primary sensorimotor cortex (PSM) in all subjects with fMRI and with PET. With both methods, 78% of all activated voxels were located in the PSM. Overlap of activated regions occurred in all subjects (mean 43%, SD 26%). The size of the activated regions in PSM with both methods was highly correlated (rho = 0.87, p < 0.01). The mean distance between centers of mass of the activated regions in the PSM for fMRI versus PET was 6.7 mm (SD 3.0 mm). Average magnitude of signal change in activated voxels in this region, expressed as z-values adapted to timeseries, zt, was similar (fMRI 5.5, PET 5.3). Results indicate that positive blood oxygen level-dependent (BOLD) signal changes obtained with 3D principles of echo shifting with a train of observations (PRESTO) fMRI are correlated with rCBF, and that sensitivity of fMRI can equal that of H215O PET.

Measuring the effects of indomethacin on changes in cerebral oxidative metabolism and cerebral blood flow during sensorimotor activation

The work presented here uses combined blood oxygenation level‐dependent (BOLD) and arterial spin tagging (AST) approaches to study the effect of indomethacin on cerebral blood flow (CBF) and oxygen consumption (CMRO2) increases during motor activation. While indomethacin reduced the CBF increase during activation, it did not significantly affect the CMRO2 increase during activation. The ratio of the activation‐induced CBF increase in the presence and absence of indomethacin was 0.54 ± 0.08 (±SEM, n = 8, P < 0.001), while the ratio of the CMRO2 increase in the presence and absence of the drug was 1.02 ± 0.08 (±SEM, N = 8, ns). Potential difficulties in estimating CMRO2 changes from combined BOLD/AST data are discussed. Magn Reson Med 50:99–106, 2003. Published 2003 Wiley‐Liss, Inc.

Noise reduction in multi-slice arterial spin tagging imaging.

Attenuating the static signal in arterial spin tagging (ASSIST) was initially developed for 3D imaging of cerebral blood flow. To enable the simultaneous collection of cerebral blood flow and BOLD data, a multi‐slice version of ASSIST is proposed. As with the 3D version, this sequence uses multiple inversion pulses during the tagging period to suppress the static signal. To maintain background suppression in all slices, the multi‐slice sequence applies additional inversion pulses between slice acquisitions. The utility of the sequence was demonstrated by simultaneously acquiring ASSIST and BOLD data during a functional task and by collecting resting‐state ASSIST data over a large number of slices. In addition, the temporal stability of the perfusion signal was found to be 60% greater at 3 T compared to 1.5 T, which was attributed to the insensitivity of ASSIST to physiologic noise. Magn Reson Med 53:735–738, 2005. Published 2005 Wiley‐Liss, Inc.

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Significance Pulsed focused ultrasound (pFUS) with systemic microbubble (MB) infusion is a noninvasive technique that opens the blood–brain barrier (BBB) and is currently advocated for increasing drug or gene delivery in neurological diseases. The opening of the BBB by pFUS+MB resulted in immediate damage-associated molecular patterns that led to a sterile inflammation response within the parenchyma that lasted 24 h. Currently, pFUS+MB exposure is under consideration as an adjuvant in the treatment in malignancy or neurodegenerative disease. These results demonstrate that pFUS+MB induces a sterile inflammatory response compatible with ischemia or mild traumatic brain injury. Further investigation will be required before translation to clinical trials. MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood–brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFα indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NFκB pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL+ neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68+ macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials.

19F magnetic resonance imaging of cerebral blood flow with 0.4-cc resolution

19F magnetic resonance imaging techniques were used to determine “wash-in” and “wash-out” curves of the inert, diffusible gas CHF3 from 0.4-cc voxels in the cat brain, and mass spectrometer gas detection was used to determine the CHF3 concentration in expired air. These two sets of data were used to calculate cerebral blood flow values in the 0.4-cc voxels, and the blood flow images were registered with high-resolution 1H magnetic resonance images. Data were collected both during the wash-in and wash-out phases of the experiment, but the two sets of data were analyzed separately to obtain independent estimates of the blood flow during the two phases, i.e., Qin and Qout. Repeated determinations of cerebral blood flow images were performed in individual animals, and the entire protocol was repeated on five different animals. The average values of Qin and Qout for a typical 0.4-cc voxel in the parietal cortex were 83 ml 100 g−1 min−1 and 72 ml 100 g−1 min−1, respectively. Monte Carlo calculations utilizing the noise in the 19F NMR signal from this voxel predict an average standard deviation for Qin and Qout of ± 10%. The average standard deviation for repeated measurements (in the same animal) of Qin and Qout in this voxel was ± 14%. We conclude that 19F magnetic resonance imaging approaches have the potential to image cerebral blood flow in humans.

Simultaneous BOLD/perfusion measurement using dual-echo FAIR and UNFAIR: sequence comparison at 1.5T and 3.0T

Functional MRI (fMRI) studies designed for simultaneously measuring Blood Oxygenation Level Dependent (BOLD) and Cerebral Blood Flow (CBF) signal often employ the standard Flow Alternating Inversion Recovery (FAIR) technique. However, some sensitivity is lost in the BOLD data due to inherent T1 relaxation. We sought to minimize the preceding problem by employing a modified UN-inverted FAIR (UNFAIR) technique, which (in theory) should provide identical CBF signal as FAIR with minimal degradation of the BOLD signal. UNFAIR BOLD maps acquired from human subjects (n = 8) showed significantly higher mean z-score of approximately 17% (p < 0.001), and number of activated voxels at 1.5T. On the other hand, the corresponding FAIR perfusion maps were superior to the UNFAIR perfusion maps as reflected in a higher mean z-score of approximately 8% (p = 0.013), and number of activated voxels. The reduction in UNFAIR sensitivity for perfusion is attributed to increased motion sensitivity related to its higher background signal, and, T2 related losses from the use of an extra inversion pulse. Data acquired at 3.0T demonstrating similar trends are also presented.

PRESTO, a Rapid 3D Approach for Functional MRI of Human Brain

Ogawa et al. [1, 2] proposed in 1990 that physiological information related to neuronal activity can be incorporated in functional magnetic resonance imaging (fMRI) based on changes in the concentration of deoxyhemoglobin in blood (blood oxygenation level dependent, or BOLD effect). As compared to positron emission tomography (PET) and single photon emission computed tomography (SPECT), BOLD fMRI offers substantial advantages: minimal discomfort, no exposure to ionizing radiation and excellent spatial and temporal resolution. Several studies have now demonstrated that sensory and language functions can be mapped with fMRI.

3D arterial spin tagging studies of cognitive activation

Introduction Although single slice arterial spin tagging approaches have been used to study focal increases in cerebral blood flow (CBF) during cognitive tasks [ 11, they do not provide adequate coverage of the brain. The application of 3D arterial spin tagging approaches to cognitive activation studies has been restricted by sensitivity limitations. However, recent studies have shown that background suppressed multi-echo techniques can increase the sensitivity of 3D arterial spin tagging approaches [2,3]. The work presented here demonstrates that multi-echo background suppressed 3D arterial spin tagging approaches can be used to quantitate focal changes in cerebral blood tlow images during cognitive tasks.