Kamil Uludag

Simultaneous PET-MRI: a new approach for functional and morphological imaging

Noninvasive imaging at the molecular level is an emerging field in biomedical research. This paper introduces a new technology synergizing two leading imaging methodologies: positron emission tomography (PET) and magnetic resonance imaging (MRI). Although the value of PET lies in its high-sensitivity tracking of biomarkers in vivo, it lacks resolving morphology. MRI has lower sensitivity, but produces high soft-tissue contrast and provides spectroscopic information and functional MRI (fMRI). We have developed a three-dimensional animal PET scanner that is built into a 7-T MRI. Our evaluations show that both modalities preserve their functionality, even when operated isochronously. With this combined imaging system, we simultaneously acquired functional and morphological PET-MRI data from living mice. PET-MRI provides a powerful tool for studying biology and pathology in preclinical research and has great potential for clinical applications. Combining fMRI and spectroscopy with PET paves the way for a new perspective in molecular imaging.

Functional localization in the human brain: gradient-echo, spin-echo, and arterial spin-labeling fMRI compared with neuronavigated TMS

A spatial mismatch of up to 14 mm between optimal transcranial magnetic stimulation (TMS) site and functional magnetic resonance imaging (fMRI) signal has consistently been reported for the primary motor cortex. The underlying cause might be the effect of magnetic susceptibility around large draining veins in Gradient‐Echo blood oxygenation level‐dependent (GRE‐BOLD) fMRI. We tested whether alternative fMRI sequences such as Spin‐Echo (SE‐BOLD) or Arterial Spin‐Labeling (ASL) assessing cerebral blood flow (ASL‐CBF) may localize neural activity closer to optimal TMS positions and primary motor cortex than GRE‐BOLD. GRE‐BOLD, SE‐BOLD, and ASL‐CBF signal changes during right thumb abductions were obtained from 15 healthy subjects at 3 Tesla. In 12 subjects, tissue at fMRI maxima was stimulated with neuronavigated TMS to compare motor‐evoked potentials (MEPs). Euclidean distances between the fMRI center‐of‐gravity (CoG) and the TMS motor mapping CoG were calculated. Highest SE‐BOLD and ASL‐CBF signal changes were located in the anterior wall of the central sulcus [Brodmann Area 4 (BA4)], whereas highest GRE‐BOLD signal changes were significantly closer to the gyral surface. TMS at GRE‐BOLD maxima resulted in higher MEPs which might be attributed to significantly higher electric field strengths. TMS‐CoGs were significantly anterior to fMRI‐CoGs but distances were not statistically different across sequences. Our findings imply that spatial differences between fMRI and TMS are unlikely to be caused by spatial unspecificity of GRE‐BOLD fMRI but might be attributed to other factors, e.g., interactions between TMS‐induced electric field and neural tissue. Differences between techniques should be kept in mind when using fMRI coordinates as TMS (intervention) targets. Hum Brain Mapp, 2011.

Quantifying the Link between Anatomical Connectivity, Gray Matter Volume and Regional Cerebral Blood Flow: An Integrative MRI Study

Background In the graph theoretical analysis of anatomical brain connectivity, the white matter connections between regions of the brain are identified and serve as basis for the assessment of regional connectivity profiles, for example, to locate the hubs of the brain. But regions of the brain can be characterised further with respect to their gray matter volume or resting state perfusion. Local anatomical connectivity, gray matter volume and perfusion are traits of each brain region that are likely to be interdependent, however, particular patterns of systematic covariation have not yet been identified. Methodology/Principal Findings We quantified the covariation of these traits by conducting an integrative MRI study on 23 subjects, utilising a combination of Diffusion Tensor Imaging, Arterial Spin Labeling and anatomical imaging. Based on our hypothesis that local connectivity, gray matter volume and perfusion are linked, we correlated these measures and particularly isolated the covariation of connectivity and perfusion by statistically controlling for gray matter volume. We found significant levels of covariation on the group- and regionwise level, particularly in regions of the Default Brain Mode Network. Conclusions/Significance Connectivity and perfusion are systematically linked throughout a number of brain regions, thus we discuss these results as a starting point for further research on the role of homology in the formation of functional connectivity networks and on how structure/function relationships can manifest in the form of such trait interdependency.

Interleaved TMS/CASL: Comparison of different rTMS protocols

Continuous Arterial Spin Labeling (CASL) offers the possibility to quantitatively measure the regional cerebral blood flow (rCBF). We demonstrate, for the first time, the feasibility of interleaving Transcranial Magnetic Stimulation (TMS) with CASL at 3 T. Two different repetitive TMS (rTMS) protocols were applied to the motor cortex in 10 subjects and the effect on rCBF was measured using a CASL sequence with separate RF coils for labeling the inflowing blood. Each subject was investigated, using a block design, under 7 different conditions: continuous 2 Hz rTMS (3 intensities: 100%, 110% and 120% resting motor threshold [MT]), short 10 Hz rTMS trains at 110% MT (8 pulses per train; 3 different numbers of trains per block with 2, 4 and 12 s intervals between trains) and volitional movement (acoustically triggered by 50% MT stimuli). We show robust rCBF increases in motor and premotor areas due to rTMS, even at the lowest stimulation intensity of 100% MT. RCBF exhibited a linear positive dependency on stimulation intensity (for continuous 2 Hz rTMS) and the number of 10 Hz trains in the stimulated M1/S1 as well as in premotor and supplementary motor areas. Interestingly, the 2 different rTMS protocols yielded markedly different rCBF activation time courses, which did not correlate with the electromyographic recordings of the muscle responses. In future, this novel combination of TMS with ASL will offer the possibility to investigate the immediate and after-effects of rTMS stimulation on rCBF, which previously was only possible using PET.

Differential effects of intranasal insulin and caffeine on cerebral blood flow

Insulin is an important modulator of brain functions such as memory and appetite regulation. Besides the effect on neuronal activity, it is also possible that insulin has a direct vasodilatory effect on cerebral blood flow (CBF). We investigated the impact of increased insulin levels in the central nervous system on basal and task‐induced CBF as well as blood oxygenation level‐dependent (BOLD) response in the visual cortex using pulsed arterial spin‐labeling MRI. An intranasal insulin application was used to avoid peripheral hyperinsulinaemia, which would lead to a cascade of hormonal changes. In a control experiment, caffeine was applied due to its well‐known impact on the vasculature of the brain leading to a reliable reduction of CBF. Eight lean subjects were included in the study. On 2 separate days, intranasal human insulin or caffeine tablets were given to the subjects after fasting over night. On each day, basal CBF and task‐induced CBF were measured before and 30 min after application of insulin or caffeine in each subject. During the task condition, a flickering checkerboard was presented. Insulin had no effect on basal CBF and task‐induced CBF in comparison with drug‐free baseline measurement in the visual cortex and control regions. After caffeine application, however, there was a significant decrease of CBF during stimulation in the visual cortex. The BOLD response was not altered by insulin or caffeine between pre‐ and postdose measurements. In conclusion, we found no evidence for a direct vasodilatory effect of intranasal insulin on the cerebral vascular system in this study. Hum Brain Mapp, 2012.

fMRI Adaptation between Action Observation and Action Execution Reveals Cortical Areas with Mirror Neuron Properties in Human BA 44/45

Mirror neurons (MNs) are considered to be the supporting neural mechanism for action understanding. MNs have been identified in monkey’s area F5. The identification of MNs in the human homolog of monkeys’ area F5 Broadmann Area 44/45 (BA 44/45) has been proven methodologically difficult. Cross-modal functional MRI (fMRI) adaptation studies supporting the existence of MNs restricted their analysis to a priori candidate regions, whereas studies that failed to find evidence used non-object-directed (NDA) actions. We tackled these limitations by using object-directed actions (ODAs) differing only in terms of their object directedness in combination with a cross-modal adaptation paradigm and a whole-brain analysis. Additionally, we tested voxels’ blood oxygenation level-dependent (BOLD) response patterns for several properties previously reported as typical MN response properties. Our results revealed 52 voxels in left inferior frontal gyrus (IFG; particularly BA 44/45), which respond to both motor and visual stimulation and exhibit cross-modal adaptation between the execution and observation of the same action. These results demonstrate that part of human IFG, specifically BA 44/45, has BOLD response characteristics very similar to monkey’s area F5.

Magnetic field distribution and signal decay in functional MRI in very high fields (up to 9.4 T) using Monte Carlo diffusion modeling

Extravascular signal decay rate R2 or R2∗ as a function of blood oxygenation, geometry, and field strength was calculated using a Monte Carlo (MC) algorithm for a wider parameter range than hitherto by others. The relaxation rates of gradient-recalled-echo (GRE) and Hahn-spin-echo (HSE) imaging in the presence of blood vessels (ranging from capillaries to veins) have been computed for a wide range of field strengths up to 9.4T and 50% blood deoxygenation. The maximum HSE decay was found to be shifted to lower radii in higher compared to lower field strengths. For GRE, however, the relaxation rate was greatest for large vessels at any field strength. In addition, assessments of computational reliability have been carried out by investigating the influence of the time step, the Monte Carlo step procedure, boundary conditions, the number of angles between the vessel and the exterior field B0, the influence of neighboring vessels having the same orientation as the central vessel, and the number of proton spins. The results were compared with those obtained from a field distribution of the vessel computed by an analytic formula describing the field distribution of an ideal object (an infinitely long cylinder). It was found that the time step is not critical for values equal to or lower than 200 microseconds. The choice of the MC step procedure (three-dimensional Gaussian diffusion, constant one- or three-dimensional diffusion step) also failed to influence the results significantly; in contrast, the free boundary conditions, as well as taking too few angles into account, did introduce errors. Next neighbor vessels with the same orientation as the main vessel did not contribute significantly to signal decay. The total number of particles simulated was also found to play a minor role in computing R2/ R2∗.