4956 3 A-C Zappe K Uludag A Oeltermann K Ugurbil NK Logothetis 2008-11-00 11 18 2666 2673 Cerebral Cortex Hypercapnia is often used as vasodilatory challenge in clinical applications and basic research. In functional magnetic resonance imaging (fMRI), elevated CO2 is applied to derive stimulus-induced changes in the cerebral rate of oxygen consumption (CMRO2) by measuring cerebral blood flow (CBF) and bloodoxygenation- level-dependent (BOLD) signal. Such methods, however, assume that hypercapnia has no direct effect on CMRO2. In this study, we used combined intracortical recordings and fMRI in the visual cortex of anesthetized macaque monkeys to show that spontaneous neuronal activity is in fact significantly reduced by moderate hypercapnia. As expected, measurement of cerebral blood volume using an exogenous contrast agent and of BOLD signal showed that both are increased during hypercapnia. In contrast to this, spontaneous fluctuations of local field potentials in the beta and gamma frequency range as well as multi-unit activity are reduced by ~15% during inhalation of 6% CO2 (pCO2 = 56 mmHg). A strong tendency toward a reduction of neuronal activity was also found at CO2 inhalation of 3% (pCO2 = 45 mmHg). This suggests that CMRO2 might be reduced during hypercapnia and caution must be exercised when hypercapnia is applied to calibrate the BOLD signal. no notspecified http://www.kyb.tuebingen.mpg.de/ published 7 15017 15421 15017 18821 4918 3 A-C Zappe K Uludag NK Logothetis 2008-09-00 7 26 961 967 Magnetic Resonance Imaging The blood oxygenation level-dependent (BOLD) signal is an indirect hemodynamic signal which is sensitive to cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen (CMRO2). Therefore, the BOLD signal amplitude and dynamics cannot be interpreted unambiguously without additional physiological measurements and, thus, there remains a need for a functional magnetic resonance imaging (fMRI) signal which is more closely related to the underlying neuronal activity. In this study, we measured cerebral blood flow with continuous arterial spin labeling, cerebral blood volume with an exogenous contrast agent and BOLD combined with intracortical electrophysiological recording in primary visual cortex of the anesthetized monkey. During inhalation of 6% CO2, it was observed that CBF and CBV are not further increased by a visual stimulus, although baseline CBF for 6% CO2 is below the maximal value of CBF. In contrast, the electrophysiological response to the stimulation was found to be preserved during hypercapnia. As a consequence, the simultaneously measured BOLD signal responds negatively to a visual stimulation for 6% CO2 inhalation in the same voxels responding positively during normocapnia. These observations suggest that the fMRI response to a sensory stimulus for 6% CO2 inhalation occurs in the absence of a hemodynamic response, and it therefore directly reflects the oxygen extraction into the tissue. no notspecified http://www.kyb.tuebingen.mpg.de/ published 6 15017 15421 15017 18821 4808 3 A-C Zappe J Pfeuffer H Merkle NK Logothetis JBM Goense 2008-03-00 3 28 640 652 Journal of Cerebral Blood Flow and Metabolism no notspecified http://www.kyb.tuebingen.mpg.de/ published 12 15017 15421 4630 3 JBM Goense A-C Zappe NK Logothetis 2007-07-00 6 25 740 747 Magnetic Resonance Imaging To understand the physiological mechanisms underlying the blood-oxygenation-level-dependent (BOLD) signal, the acquisition of data must be optimized to achieve the maximum possible spatial resolution and specificity. The term “specificity” implies the selective enhancement of signals originating in the parenchyma, and thus best reflecting actual neural activity. Such spatial specificity is a prerequisite for imaging aimed at the elucidation of interactions between cortical micromodules, such as columns and laminae. In addition to the optimal selection of functional magnetic resonance imaging pulse sequences, accurate superposition of activation patterns onto corresponding anatomical scans, preferably acquired during the same experimental session, is necessary. At high resolution, exact functional-to-structural registration is of critical importance, because even small differences in geometry, that arise when different sequences are used for functional and anatomical scans, can lead to misallocation of activ ation and erroneous interpretation of data. In the present study, we used spin-echo (SE) echo planar imaging (EPI) for functional scans, since the SE-BOLD signal is sensitive to the capillary response, together with SE-EPI anatomical reference scans. The combination of these acquisition methods revealed a clear spatial colocalization of the largest fractional changes with the Gennari line, suggesting peak activity in Layer IV. Notably, this very same layer coincided with the largest relaxivity changes as observed in steady-state cerebral blood volume measurements, using the intravascular agent monocrystalline iron oxide nanoparticles (MION). no notspecified http://www.kyb.tuebingen.mpg.de/ published 7 15017 15421 4288 3 A-C Zappe J Reichold C Burger B Weber A Buck J Pfeuffer NK Logothetis 2007-07-00 6 25 775 783 Magnetic Resonance Imaging Noninvasive absolute quantification of cerebral blood flow (CBF) with high spatial resolution is still a challenging task. Arterial spin labeling (ASL) is a promising magnetic resonance imaging (MRI) method for accurate perfusion quantification. However, modeling of ASL data is far from being standardized and has not been investigated in great detail. In this study, two-compartment modeling of monkey ASL data in three physiological conditions (baseline, sensory activated and globally elevated CBF) is reported. Absolute perfusion and arterial transit times were derived for gray matter (GM) and white matter (WM) separately. The uncertainties of the model‘s result were determined by Monte Carlo simulations. The fitted CBF values for GM were 133 ml/min/100 ml at baseline condition, 165 ml/min/100 ml during visual stimulation and 234 ml/min/100 ml for globally elevated CBF after intravenous injection of acetazolamide. The ratio of GM to WM CBF was 2.5 at baseline and was found to d ecre ase to 1 .6 after application of acetazolamide. The corresponding arterial transit times decreased from 742 to 607 ms in GM and from 985 to 875 ms in WM. Monte Carlo simulations showed that absolute CBF values can be determined with an error of 11–15%, while the arterial transit time values have a coefficient of variation of 25–31%. With an alternative acquisition scheme, the precision of the arterial transit times can be improved significantly. The CBF values in the occipital lobe of the monkey brain quantified with ASL are higher than previously reported in positron emission tomography studies. no notspecified http://www.kyb.tuebingen.mpg.de/ published 8 15017 15421 2622 3 AC Zappe T Maucher K Meier C Scheiber 2004-04-00 4 51 828 834 Magnetic Resonance for Medicine Functional magnetic resonance imaging (fMRI) experiments on tactile perception are difficult to perform because the special characteristics of an MRI environment restrict the experimental setup. Although recently developed actuators have made it possible to apply vibrotactile stimuli to the skin during an fMRI experiment, the projection of spatially extended patterns is still precluded. In order to examine the processing of tactile perception, a new pneumatically-driven tactile device (PTD) has been built. This device is capable of stimulating the skin, using arbitrary time sequences that consist of 2D tactile images up to 64 pixels. It is shown how the device is implemented in a 2 T fMRI environment, and show that it operates without generating artifacts. Dedicated software allows the generation of complex paradigms and provides a user-friendly interface to other brain mapping systems, as well as automated operation. This paper describes the PTD elucidates its features, and demonstrate its reliability by reporting results from an fMRI study based on an event-related protocol involving six subjects. no notspecified http://www.kyb.tuebingen.mpg.de/ published 6 UludagZGL2009 7 K Uludag A-C Zappe J Goense NK Logothetis Honolulu, HI, USA2009-04-00 17th Annual Meeting of the International Society for Magnetic Resonance in Medicine (ISMRM 2009) A BOLD signal model as a function oxygen extraction fraction and CBV was developed in order to determine change in oxidative metabolism from combined BOLD signal and CBF measurements. The new model is an alternative model to the widely used calibrated BOLD approach initally proposed by Davis and colleagues for GRE at 1.5T. The new model, however, takes also intra-vascular MRI signal into account and is developed for both GRE and SE from 1.5T up to 16.4T. In the current study, at 4.7T and 7T using SE and GRE, oxidative metabolism change during visual stimulation was determined in macaque monkeys. no notspecified http://www.kyb.tuebingen.mpg.de/fileadmin/user_upload/files/publications/ISMRM-2009-03701.pdf published 0 15017 15421 5860 7 A-C Zappe NK Logothetis Santorini, Greece2008-06-00 104 AREADNE 2008: Research in Encoding and Decoding of Neural Ensembles no notspecified http://www.kyb.tuebingen.mpg.de/ published -104 15017 15421 ZappeUL2008 7 A-C Zappe K Uludag NK Logothetis Toronto, Canada2008-05-00 166 16th Scientific Meeting and Exhibition of the International Society of Magnetic Resonance in Medicine (ISMRM 2008) The BOLD signal is sensitive to cerebral blood flow (CBF), blood volume (CBV) and oxygen extraction. In the anesthetized monkey, we observe a vasodilatory ceiling effect during inhalation of 6% CO2 where CBF or CBV are not further increased by visual stimulation. In contrast, simultaneously measured local field potential responds to the stimulation as strong as during normocapnia. As a consequence, the stimulus-induced fMRI response during 6% hypercapnia has been found to be negative reflecting only the oxygen extraction from the blood. With this method, oxygen extraction can be imaged by means of fMRI without injection of an exogenous drug. no notspecified http://www.kyb.tuebingen.mpg.de/fileadmin/user_upload/files/publications/ISMRM-2008-00850.pdf published -166 15017 15421 4694 7 A-C Zappe JBM Goense NK Logothetis San Diego, CA, USA2007-11-00 37th Annual Meeting of the Society for Neuroscience (Neuroscience 2007) Using perfusion MRI with continuous arterial spin labeling (CASL) cerebral blood flow (CBF) can be measured directly at the capillary level [1]. The common belief is that perfusion MRI is more closely related to the neural activity than most functional MR imaging methods. It has successfully been used to reveal orientation columns in the cat, on the scale of ~1 mm [2]. It has been shown that the BOLD signal is higher in layer IV than in supra- and infragranular layers [3]. Since the BOLD contrast is a combination of several signals, we want to determine whether this reflects depth-dependent changes in CBF. Moreover, functional CBF (fCBF) can be interleaved with BOLD in the same scan to compute changes in oxygen consumption rate (CMRO2). We use striate cortex of the monkey which has a well-defined laminar structure, allowing determination of the precise location of functional CBF changes. MR imaging was performed on healthy adult monkeys (macaca mulatta) using a vertical 4.7T/40 cm primate scanner (Bruker Biospec) as described previously [4]. A saddle-shaped volume coil was used in combination with a 25 mm receive surface coil, and a cravat-shaped label coil for CASL, placed around the neck of the monkey. A labeling pulse of 2 s was followed by 200 or 800 ms postlabel delay (PLD), and images were acquired using a segmented, multi-slice GE-EPI with in-plane resolution of 375x333 μm and TE/TR of 11/3000 ms. The visual stimulus was a full field rotating checkerboard presented to both eyes. All data analysis was performed in MatLab (the Mathworks). We obtained robust high resolution fCBF maps in visual cortex with a signal-to-noise ratio of 25. The laminar profile of % fCBF obtained at 800 ms shows a clear peak at the level of the Gennari-line, i.e. in layer IV. At a short PLD a contribution from the larger pial vessels was seen in addition to a narrow peak in layer IV. The location of the cortical surface and the Gennari-line were identified based on anatomical scans. The PLD determines the relative contributions of the different vascular compartments. For scans with a sufficiently long PLD the functional signal represents the capillary fraction. For short PLDs our data show a contribution of arterioles to the fCBF map as hypothesized in [5]. Peak fCBF was observed in layer IV similar to the BOLD-results, possibly representing the higher metabolic activity of layer IV. In combination with calibrated BOLD this will allow determination of CMRO2 in vivo at high spatial resolution. no notspecified http://www.kyb.tuebingen.mpg.de/ published 0 15017 15421 4428 7 A-C Zappe NK Logothetis JBM Goense Berlin, Germany2007-05-00 136 2007 Joint Annual Meeting ISMRM-ESMRMB High resolution fMRI allows us to determine more accurately the origins of the fMRI signal. This has shown that even at high field, the GE-BOLD signal has still a large vascular contribution [1]. Alternative methods like SE- and monocrystalline iron oxide nanocolloid (MION)-based methods have been shown to be spatially more specific than conventional BOLD, and are able to reveal functional subunits in the cortex [2-6]. Here we compare the specificity of BOLD and CBV fMRI methods in the macaque; its striate cortex shows very obvious laminar structure in anatomical images, allowing accurate determination of the precise location of the fMRI activation. no notspecified http://www.kyb.tuebingen.mpg.de//fileadmin/user_upload/files/publications/ISMRM2007-Zappe_4428[0].pdf published -136 15017 15421 3970 7 A Zappe H Merkle J Pfeuffer NK Logothetis Seattle, WA, USA2006-05-00 419 14th Scientific Meeting of the International Society of Magnetic Resonance in Medicine (ISMRM 2006) Perfusion-based imaging in the monkey primary visual cortex was performed at 7 T applying continuous arterial spin labeling (CASL). Increased perfusion sensitivity and SNR at high magnetic field (due to larger T1) was further optimized using a custom-made three-coil setup with a separate neck labeling coil. We investigated the labeling parameters to obtain relative fCBF changes in the anaesthetized monkey. We report excellent functional activation of striate cortex at high resolution of 0.75x0.9mm2 in-plane. Interestingly, the optimal parameter set for obtaining highest signal changes of rCBF are different from the reported values for imaging gray matter CBF. no notspecified http://www.kyb.tuebingen.mpg.de//fileadmin/user_upload/files/publications/ISMRMproc_abstract_3970[0].pdf published -419 15017 15421 3364 7 AC Zappe H Merkle NK Logothetis J Pfeuffer Miami Beach, FL, USA2005-05-00 262 13th Scientific Meeting of the International Society of Magnetic Resonance in Medicine (ISMRM 2005) CASL experiments in the monkey brain were performed at 4.7 T and 7 T using a separate labeling coil. Increased sensitivity and SNR were achieved by a custom-made three-coil setup and high magnetic field with its increased T1. We report the development and optimization of the setup and first experiments in the monkey (macaca mulatta). Parameters for continuous labeling (label power, label duration, post label delay) were optimized to measure gray matter rCBF and fCBF changes, reporting excellent multi-slice coverage at high resolution of 0.75 – 1 mm in-plane. no notspecified http://www.kyb.tuebingen.mpg.de//fileadmin/user_upload/files/publications/pdf3364.pdf published -262 15017 15421 2861 7 AC Zappe H Merkle NK Logothetis J Pfeuffer Copenhagen, Denmark2004-09-00 66 67 21st Annual Scientific Meeting of the ESMRMB 2004 Arterial spin labeling is commonly used to measure cerebral blood flow (CBF) in the brain. Since CBF signal is intrinsically low, optimization of the signal-to-noise ratio (SNR) is critical. CASL with a separate labeling coil has the advantages of increased SNR, multi-slice capability, and absence of magnetization transfer. The CASL method has been applied successfully in rats1-3, and in human studies4. Its wider application especially on routine human MR systems is hindered by the advanced hardware and software requirements. Here, we report the development of CASL for use on monkeys. Increased sensitivity (SNR) was achieved because of utilization of an custom-made three-coil setup and the use of high magnetic field (7T) with its favorable T1. The feasibility of this approach is demonstrated with a flow phantom and with initial experiments in the monkey. no notspecified http://www.kyb.tuebingen.mpg.de//fileadmin/user_upload/files/publications/pdf2861.pdf published 1 15017 15421 4290 10 J Reichold A-C Zappe C Burger B Weber A Buck J Pfeuffer NK Logothetis 4158 10 A-C Zappe JBM Goense NK Logothetis J Pfeuffer 3841 10 A-CC Zappe K Uludaq G Rainer NK Logothetis ZappeMLP2004 10 A-C Zappe H Merkle NK Logothetis J Pfeuffer