Precision fMRI and cluster-failure in the individual brain.

Advances in neuroimaging acquisition protocols and denoising techniques, along with increasing magnetic field strengths, have dramatically improved the temporal signal-to-noise ratio (tSNR) in functional magnetic resonance imaging (fMRI). This permits spatial resolution with submillimeter voxel sizes and ultrahigh temporal resolution and opens a route toward performing precision fMRI in the brains of individuals. Yet ultrahigh spatial and temporal resolution comes at a cost: it reduces tSNR and, therefore, the sensitivity to the blood oxygen level-dependent (BOLD) effect and other functional contrasts across the brain. Here we investigate the potential of various smoothing filters to improve BOLD sensitivity while preserving the spatial accuracy of activated clusters in single-subject analysis. We introduce adaptive-weight smoothing with optimized metrics (AWSOM), which addresses this challenge extremely well. AWSOM employs a local inference approach that is as sensitive as cluster-corrected inference of data smoothed with large Gaussian kernels, but it preserves spatial details across multiple tSNR levels. This is essential for examining whole-brain fMRI data because tSNR varies across the entire brain, depending on the distance of a brain region from the receiver coil, the type of setup, acquisition protocol, preprocessing, and resolution. We found that cluster correction in single subjects results in inflated family-wise error and false positive rates. AWSOM effectively suppresses false positives while remaining sensitive even to small clusters of activated voxels. Furthermore, it preserves signal integrity, that is, the relative activation strength of significant voxels, making it a valuable asset for a wide range of fMRI applications. Here we demonstrate these features and make AWSOM freely available to the research community for download.

Somatosensory BOLD fMRI reveals close link between salient blood pressure changes and the murine neuromatrix.

The neuromatrix, or "pain matrix", is a network of cortical brain areas which is activated by noxious as well as salient somatosensory stimulation. This has been studied in mice and humans using blood oxygenation level-dependent (BOLD) fMRI. Here we demonstrate that BOLD effects observed in the murine neuromatrix in response to salient somatosensory stimuli are prone to reflect mean arterial blood pressure (MABP) changes, rather than neural activity. We show that a standard electrostimulus typically used in murine somatosensory fMRI can induce substantial elevations in MABP. Equivalent drug-induced MABP changes - without somatosensory stimulation - evoked BOLD patterns in the neuromatrix strikingly similar to those evoked by electrostimulation. This constitutes a serious caveat for murine fMRI. The regional specificity of these BOLD patterns can be attributed to the co-localization of the neuromatrix with large draining veins. Based on these findings we propose a cardiovascular support mechanism whereby abrupt elevations in MABP provide additional energy supply to the neuromatrix and other essential brain areas in fight-or-flight situations.

Cerebral blood volume estimation by ferumoxytol-enhanced steady-state MRI at 9.4 T reveals microvascular impact of α1 -adrenergic receptor antibodies.

Cerebrovascular abnormality is frequently accompanied by cognitive dysfunctions, such as dementia. Antibodies against the α1 -adrenoceptor (α1 -AR) can be found in patients with Alzheimer's disease with cerebrovascular disease, and have been shown to affect the larger vessels of the brain in rodents. However, the impact of α1 -AR antibodies on the cerebral vasculature remains unclear. In the present study, we established a neuroimaging method to measure the relative cerebral blood volume (rCBV) in small rodents with the ultimate goal to detect changes in blood vessel density and/or vessel size induced by α1 -AR antibodies. For this purpose, mapping of R2 * and R2 was performed using MRI at 9.4 T, before and after the injection of intravascular iron oxide particles (ferumoxytol). The change in the transverse relaxation rates (ΔR2 *, ΔR2 ) showed a significant rCBV decrease in the cerebrum, cortex and hippocampus of rats (except hippocampal ΔR2 ), which was more pronounced for ΔR2 * than for ΔR2 . Immunohistological analyses confirmed that the α1 -AR antibody induced blood vessel deficiencies. Our findings support the hypothesis that α1 -AR antibodies lead to cerebral vessel damage throughout the brain, which can be monitored by MRI-derived rCBV, a non-invasive neuroimaging method. This demonstrates the value of rCBV estimation by ferumoxytol-enhanced MRI at 9.4 T, and further underlines the significance of this antibody in brain diseases involving vasculature impairments, such as dementia.

Myocardial Effective Transverse Relaxation Time T 2* is Elevated in Hypertrophic Cardiomyopathy: A 7.0 T Magnetic Resonance Imaging Study.

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the myocardium and bares the risk of progression to heart failure or sudden cardiac death. Identifying patients at risk remains an unmet need. Recognizing the dependence of microscopic susceptibility on tissue microstructure and on cardiac macromorphology we hypothesized that myocardial T2* might be altered in HCM patients compared to healthy controls. To test this hypothesis, myocardial T2*-mapping was conducted at 7.0 Tesla to enhance T2*-contrast. 2D CINE T2*-mapping was performed in healthy controls and HCM patients. To ensure that T2* is not dominated by macroscopic magnetic field inhomogeneities, volume selective B0 shimming was applied. T2* changes in the interventricular septum across the cardiac cycle were analyzed together with left ventricular radius and ventricular septal wall thickness. The results show that myocardial T2* is elevated throughout the cardiac cycle in HCM patients compared to healthy controls. A mean septal T2* = 13.7 ± 1.1 ms (end-systole: T2*,systole = 15.0 ± 2.1, end-diastole: T2*,diastole = 13.4 ± 1.3 ms, T2*,systole/T2*,diastole ratio = 1.12) was observed in healthy controls. For HCM patients a mean septal T2* = 17.4 ± 1.4 ms (end-systole: T2*,systole = 17.7 ± 1.2 ms, end-diastole: T2*,diastole = 16.2 ± 2.5 ms, T2*,systole/T2*,diastole ratio = 1.09) was found. Our preliminary results provide encouragement that assessment of T2* and its changes across the cardiac cycle may benefit myocardial tissue characterization in HCM.

Normothermic Mouse Functional MRI of Acute Focal Thermostimulation for Probing Nociception.

Combining mouse genomics and functional magnetic resonance imaging (fMRI) provides a promising tool to unravel the molecular mechanisms of chronic pain. Probing murine nociception via the blood oxygenation level-dependent (BOLD) effect is still challenging due to methodological constraints. Here we report on the reproducible application of acute noxious heat stimuli to examine the feasibility and limitations of functional brain mapping for central pain processing in mice. Recent technical and procedural advances were applied for enhanced BOLD signal detection and a tight control of physiological parameters. The latter includes the development of a novel mouse cradle designed to maintain whole-body normothermia in anesthetized mice during fMRI in a way that reflects the thermal status of awake, resting mice. Applying mild noxious heat stimuli to wildtype mice resulted in highly significant BOLD patterns in anatomical brain structures forming the pain matrix, which comprise temporal signal intensity changes of up to 6% magnitude. We also observed sub-threshold correlation patterns in large areas of the brain, as well as alterations in mean arterial blood pressure (MABP) in response to the applied stimulus.