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AIM: To evaluate the potential of real-time phase-contrast flow magnetic resonance imaging (MRI) at 40 ms resolution for the simultaneous determination of blood flow in the ascending aorta (AA) and superior vena cava (SVC) in response to reduced intrathoracic pressure (Mueller manoeuvre). MATERIALS AND METHODS: Through-plane flow was assessed in 20 healthy young subjects using real-time phase-contrast MRI based on highly undersampled radial fast low-angle shot (FLASH) with image reconstruction by regularized non-linear inversion. Haemodynamic alterations (three repetitions per subject = 60 events) were evaluated during normal breathing (10 s), inhalation with nearly closed epiglottis (10 s), and recovery (20 s). RESULTS: Relative to normal breathing and despite interindividual differences, reduced intrathoracic pressure by at least 30 mmHg significantly decreased the initial peak mean velocity (averaged across the lumen) in the AA by -24 ± 9% and increased the velocity in the SVC by +28 ± 25% (p < 0.0001, n = 23 successful events). Respective changes in flow volume per heartbeat were -25 ± 9% in the AA and +49 ± 44% in the SVC (p < 0.0001, n = 23). Flow parameters returned to baseline during sustained pressure reduction, while the heart rate was elevated by 10% (p < 0.0001) after the start (n = 24) and end (n = 17) of the manoeuvre. CONCLUSIONS: Real-time flow MRI during low intrathoracic pressure non-invasively revealed quantitative haemodynamic adjustments in both the AA and SVC.

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OBJECTIVE: Real-time phase-contrast flow MRI at high spatiotemporal resolution was applied to simultaneously evaluate haemodynamic functions in the ascending aorta (AA) and superior vena cava (SVC) during elevated intrathoracic pressure (Valsalva manoeuvre). METHODS: Real-time phase-contrast flow MRI at 3 T was based on highly undersampled radial gradient-echo acquisitions and phase-sensitive image reconstructions by regularized non-linear inversion. Dynamic alterations of flow parameters were obtained for 19 subjects at 40-ms temporal resolution, 1.33-mm in-plane resolution and 6-mm section thickness. Real-time measurements were performed during normal breathing (10 s), increased intrathoracic pressure (10 s) and recovery (20 s). RESULTS: Real-time measurements were technically successful in all volunteers. During the Valsalva manoeuvre (late strain) and relative to values during normal breathing, the mean peak flow velocity and flow volume decreased significantly in both vessels (p < 0.001) followed by a return to normal parameters within the first 10 s of recovery in the AA. By contrast, flow in the SVC presented with a brief (1-2 heartbeats) but strong overshoot of both the peak velocity and blood volume immediately after pressure release followed by rapid normalization. CONCLUSION: Real-time phase-contrast flow MRI may assess cardiac haemodynamics non-invasively, in multiple vessels, across the entire luminal area and at high temporal and spatial resolution. ADVANCES IN KNOWLEDGE: Future clinical applications of this technique promise new insights into haemodynamic alterations associated with pre-clinical congestive heart failure or diastolic dysfunction, especially in cases where echocardiography is technically compromised.

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The definition of objective and effective thresholds in MRI of human brain function is a crucial step in the analysis of paradigm-related activations. This paper introduces a user-independent and robust procedure that calculates statistical parametric maps based on correlation coefficients. Thresholds are introduced as p values and defined with respect to the physiologic noise distribution of the individual maps. Experimental examples from the human visual and motor system rely on dynamic acquisitions of gradient-echo echo-planar images (2.0 T, TR = 2,000 ms, 96 x 128 matrix) with blood oxygenation level-dependent contrast. The results demonstrate the disadvantages of thresholding with fixed correlation coefficients. In contrast, taking the individual noise into account allows for a derivation of p values and a reliable identification of highly significant activation centers. An adequate delineation of the spatial extent of activation may be achieved by adding directly neighboring pixels provided their correlation coefficients comply with a second lower p value threshold.

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In view of an increasing number of publications that deal with functional mapping of the human amygdala using blood oxygenation-level-dependent (BOLD) magnetic resonance imaging, we reevaluated the underlying image quality of T2*-weighted echoplanar imaging (EPI) and fast low angle shot (FLASH) sequences at 2.0-T with regard to susceptibility-induced signal losses and geometric distortions. Apart from the timing of the gradient echoes, the degree of susceptibility influences is controlled by the image voxel size. Whereas published amygdala studies report voxel sizes ranging from 22 to 125 microl, the present results suggest that reliable imaging of the amygdala with BOLD sensitivity requires voxel sizes of 4 to 8 microl or less. Preferentially, acquisitions should be performed with a coronal section orientation. Although high-resolution BOLD MRI is at the expense of temporal resolution and volume coverage, it seems to provide the only solution to this physical problem.

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Visual episodic memory encoding was investigated using echoplanar magnetic resonance imaging at 2.0 x 2.0 mm2 resolution and 1.0 mm section thickness, which allows for functional mapping of hippocampal, parahippocampal, and ventral occipital regions with reduced magnetic susceptibility artifact. The memory task was based on 54 image pairs each consisting of a complex visual scene and the face of one of six different photographers. A second group of subjects viewed the same set of images without memory instruction as well as a reversing checkerboard. Apart from visual activation in occipital cortical areas, episodic memory encoding revealed consistent activation in the parahippocampal gyrus but not in the hippocampus proper. This finding was most prominently evidenced in sagittal maps covering the right hippocampal formation. Mean activated volumes were 432 +/- 293 microl and 259 +/- 179 microl for intentional memory encoding and non-instructed viewing, respectively. In contrast, the checkerboard paradigm elicited pure visual activation without parahippocampal involvement.

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We evaluated two methods for correcting inhomogeneity-induced signal losses in magnetic resonance gradient-echo imaging that either use gradient compensation or simply acquire thin sections. The strategies were tested in the human brain in terms of achievable quality of T2*-weighted images at the level of the hippocampus and of functional activation maps of the visual cortex. Experiments were performed at 2.0 T and based on single-shot echo-planar imaging at 2. 0 x 2.0 mm(2) resolution, 4 mm section thickness, and 2.0 s temporal resolution. Gradient compensation involved a sequential 16-step variation of the refocusing lobe of the slice-selection gradient (TR/TE = 125/53 ms, flip angle 15 degrees ), whereas thin sections divided the 4-mm target plane into either four 1-mm or eight 0.5-mm interleaved multislice acquisitions (TR/TE = 2000/54 ms, flip angle 70 degrees ). Both approaches were capable of alleviating the inhomogeneity problem for structures in the base of the brain. When compared to standard 4-mm EPI, functional mapping in the visual cortex was partially compromised because of a lower signal-to-noise ratio of inhomogeneity-corrected images by either method. Relative to each other, consistently better results were obtained with the use of contiguous thin sections, in particular for a thickness of 1 mm. Multislice acquisitions of thin sections require minimal technical adjustments.

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The effects of pharmacologic depression and stimulation of cerebral activity were investigated in seven healthy young volunteers using blood oxygenation-sensitive MRI at 2.0 T. Dynamic gradient-echo imaging (7 min) was performed before, during and after the intravenous application of 10 mg diazepam and 15 mg metamphetamine as well as of the corresponding drug placebos (isotonic saline) in a brain section covering frontotemporal gray matter, subcortical gray matter structures, and cerebellum. The MRI responses were significantly different for the two drugs applied (p = 0.01). Relative to signal strength during injection, metamphetamine elicited a signal increase of 0.97 +/- 0.03% (mean +/- SD, p = 0.02) within the whole section 4-5 min after injection. Similarly, both placebo conditions led to a small signal increase, i.e. 0.50 +/- 0. 03% (n.s.) for the metamphetamine placebo and 0.40 +/- 0.07% (p = 0. 03) for the diazepam placebo. Diazepam abolished this signal increase. A topographic analysis revealed the metamphetamine-induced signal increase to be more pronounced in subcortical gray matter structures (p = 0.01) and cerebellum (p = 0.02) than in frontotemporal cortical gray matter (p = 0.04). This finding is in agreement with the hypothesis that pertinent responses not only reflect global cerebral hemodynamic adjustments, but also localized perfusion changes coupled to alterations in synaptic activity. The occurrence of a placebo response is best explained by expectancy and may provide a confounding factor in the design of functional activation experiments.

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We studied the effect of stimulus quality on the basic physiological response characteristics of oxygenation-sensitive MRI signals. Paradigms comprised a contrast-reversing checkerboard vs. darkness or vs. gray light as well as gray light vs. darkness in a 2 s/52 s protocol (nine subjects). MRI was performed at 2.0 T using single-shot gradient-echo EPI (TR/TE = 500/54 ms, flip angle 30 degrees). All paradigms elicited almost identical signal intensity time courses comprising a latency period (1-2s), an activation-induced signal increase (4-4.5% at about 6-7 s after stimulus onset) and a post-stimulus signal undershoot (-1%) that slowly recovered to baseline (about 50 s). Thus, in contrast to findings for sustained stimulation, brief presentations of distinct visual stimuli exhibit similar physiological response characteristics that support the use of a uniform response profile for the evaluation of event related paradigms.

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Magnetic resonance imaging (MRI) of neuronal "activation" relies on the elevation of blood flow and oxygenation and a related increase of the blood oxygenation level-dependent (BOLD) MRI signal. Because most cognitive paradigms involve both switches from a low degree of activity to a high degree of activity and vice versa, we have undertaken a baseline study of the temporal and spatial characteristics of positive and negative BOLD MRI responses in human visual cortex. Experiments were performed at 2.0 T using a multislice gradient-echo EPI sequence (TR = 1 s, mean TE = 54 ms, flip angle 50 degrees) at 2x2-mm2 spatial resolution. Activation and "deactivation" processes were accomplished by reversing the order of stimulus presentations in paradigms using homogeneous gray light and an alternating checkerboard as distinct functional states. For sustained stimulation (> or = 60 s) the two conditions resulted in markedly different steady-state BOLD MRI signal strengths. The transient responses to brief stimulation (< or = 18 s) differed insofar as activation processes temporally separate positive BOLD and negative undershoot effects by about 10 s, whereas negative BOLD effects and undershoot contributions overlap for deactivation processes. Apart from differences in stimulus features (e.g., motion) the used activation and deactivation protocols revealed similar maps of neuronal activity changes.

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The temporal and spatial characteristics of oxygenation-sensitive MRI responses to very brief visual stimuli (five Hz reversing black and white checkerboard pattern versus darkness) were investigated (nine subjects) by means of serial single-shot gradient-echo echo-planar imaging (2.0 T, TR=400 ms, mean TE=54 ms, flip angle 30 degrees). The use of a 0.2-s stimulus and a 90-s control phase resulted in an initial latency phase (about 2 s, no signal change), a positive MRI response (2.5% signal increase peaking at 5 s after stimulus onset), and a post-stimulus undershoot (1% signal decrease peaking at 15 s after stimulus onset) lasting for about 50-60 s. The finding that a subsecond visual stimulus elicits both a strong positive MRI response and a long-lasting undershoot provides further evidence for the neuronal origin of slow signal fluctuations seen in the absence of functional challenge and their utility for mapping functional connectivity. The additional observation that a reduction of the inter-stimulus control phase from 90 s to 9.8 s does not seem to affect the spatial extent of cortical activation in pertinent maps is of major relevance for the design and analysis of "event-related" MRI studies.

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In order to substantiate event related paradigms in magnetic resonance functional neuroimaging, we assessed the temporal and spatial characteristics of oxygenation-sensitive MRI responses to 1 s periods of visual activation in repetitive protocols. A main finding is a reduction of the functional contrast between conditions (reversing checkerboard vs. darkness) for decreasing interstimulus intervals yielding 4.5% signal change for 89 s, 4% for 9 s, 3% for 6 s, and 1% for 3 s, respectively. Although rapid repetitions of identical stimuli preclude the development of the full positive and negative MRI signal deflections, pertinent responses leave the spatial pattern of activated brain regions unaffected and result in identical maps. These findings suggest the use of interstimulus intervals of the order of the response time from stimulus onset to maximum signal strength (5-6 s in the visual system). The resulting distinction in time will allow for separate mapping of stimulus-related responses with spatially overlapping cortical representations.

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Series of single-shot blipped echo-planar images with spin-density weighting and T2* sensitivity (2.0 T, TR = 400 ms, TE = 54 ms, flip angle = 30 degrees) were used to study the temporal response profiles to repetitive visual activation (5 Hz, reversing black and white checkerboard versus darkness) for protocols comprising multiple cycles of a 1.6-s stimulus in conjunction with a 8.4-s or 90-s recovery phase and a 10-s stimulus with a 20-s or 90-s recovery phase. Analysis of the real-time data from all activated pixels resulted in a strong positive MRI response (mean values 3-6%) as well as a marked poststimulus undershoot (mean values 1-2%, duration 60-90 s) for all paradigms. Repetitive protocols with insufficient recovery periods of 8.4 s or 20 s gave rise to a wraparound effect when analyzing time-locked averages from multiple activation cycles. This problem may lead to an early signal decrease that originates from the ongoing undershoot of preceding activations folded back into the initial latency phase of a subsequent activation. When ensuring complete decoupling of responses to successive stimuli by using a 90-s recovery period, the wraparound effect vanished and an initial dip was observed in one of seven subjects for a 10-s/90-s protocol.

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Functional responses to either brief repetitive or sustained activation of the human visual cortex (movie presentation) were monitored using both fast low angle shot and echo planar imaging sequences. To allow for proper comparisons, native image contrasts were equally sensitized to changes in cerebral blood oxygenation with other experimental conditions matched as much as possible. Putative influences of receiver bandwidth and absolute voxel size were specifically addressed. In all cases resulting correlation maps and regional signal intensity time courses showed excellent spatial and temporal congruence, respectively. In particular, for a 6 min protocol of sustained activation, both FLASH and EPI yielded an initial signal increase (oxygenation overshoot), a subsequent signal decrease during ongoing stimulation, and a marked signal drop (oxygenation undershoot) after the end of stimulation. These findings exclude technical differences between FLASH and EPI as the source of previous contradictory observations more likely to be explained by differences in stimulus design.

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Stimulus-related changes in cerebral blood oxygenation were measured using high-resolution functional magnetic resonance imaging sequentially covering visual occipital areas in contiguous sections. During dynamic imaging, healthy subjects silently viewed pseudowords, single false fonts, or length-matched strings of the same false fonts. The paradigm consisted of a sixfold alternation of an activation and a control task. With pseudowords as activation vs single false fonts as control, responses were seen mainly in medial occipital cortex. These responses disappeared when pseudowords were alternated with false font strings as the control and reappeared when false font strings instead of pseudowords served as activation and were alternated with single false fonts. The string-length contrast alone, therefore, is sufficient to account for the activation pattern observed in medial visual cortex when word-like stimuli are contrasted with single characters.

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Together, the present results on oxygenation, flow, and metabolism indicate that the prevalence of nonoxidative glycolysis and associated lactate production during the initial phase of activation is replaced by the upregulation of oxidative glucose consumption (see sketches in Fig. 5). Following rapid circulatory changes the gap between oxygen availability and oxygen consumption gradually closes until a recoupling of perfusion and oxidative metabolism is achieved a few minutes after switching the state of neural activity. While brain glucose and lactate concentrations reflect an initial prevalence of anaerobic glycolysis, the changes in blood oxygenation suggest that the rapid adjustment of blood flow (enhanced oxygen delivery) is followed by a slower upregulation of oxidative metabolism (enhanced oxygen consumption). The physiological uncoupling of perfusion and oxidative metabolism emerges as a transient phenomenon in response to both onset and end of stimulation. Recoupling at enhanced cerebral metabolic rates of oxygen (CMRO2) and glucose occurs a few minutes after switching the state of neural activity. Since glycolysis takes place primarily in astrocytes, the stimulus-related increase and decrease of lactate seen here may reflect a transfer of astrocytic lactate to neurons where it is converted into pyruvate and channelled into oxidative phosphorylation. This model of metabolic responses to functional activation is supported by a recently detected pathway for glutamate-stimulated glycolysis in astrocytes that provides a simple mechanism linking astrocytic glucose utilization to neuronal activity (Pellerin and Magistretti, 1994). In summary, evidence has accumulated that the physiological uncoupling of perfusion and oxidative metabolism associated with the onset of functional activation is a transient phenomenon leading to an only temporal mismatch of oxygen delivery and consumption. Recoupling at enhanced though balanced levels of glucose and oxygen consumption is most remarkably documented by the pronounced "negative" uncoupling at the end of stimulation.

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Changes in cerebral blood oxygenation due to functional activation of the primary sensorimotor cortex during a unilateral finger opposition task were simultaneously mapped by deoxyhemoglobin-sensitive magnetic resonance imaging (MRI) and monitored by near-infrared spectroscopy (NIRS). Activation foci along the contralateral central sulcus displayed task-associated increases in MRI signal intensity, indicating a concomitant decrease of the focal concentration of deoxyhemoglobin. This interpretation was confirmed by simultaneous reductions in deoxyhemoglobin measured optically. Since observation of the latter effect required exact spatial matching of the MRI-detected activation foci and position of the fiber optic bundles ("optodes") used for transmitting and receiving light, it may be concluded that optical recordings of changes in deoxyhemoglobin during functional challenge probe only a restricted brain tissue region. While deoxyhemoglobin responses seen by NIRS were smaller for ipsi- than for contralateral finger movements, task-related increases in oxyhemoglobin were rather similar between both conditions and, thus, seem to be less specific. Furthermore, no consistent changes were obtained for total hemoglobin during task performance, possibly due to the short timing of the repetitive protocol. In general, results underline, in humans, the hitherto assumed signal physiology for functional brain mapping by oxygenation-sensitive MRI and allow assessment of both constraints and practicability of functional studies by NIRS.

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Changes in glucose consumption, lactate production, and blood oxygenation were measured during prolonged neuronal activation (4-6 min) in human primary visual cortex using dynamic magnetic resonance spectroscopy and imaging. A decrease of steady-state glucose by 40% because of enhanced use by 21% was accompanied by a transient accumulation of lactate with a peak value of 170% 2.5 min after stimulation onset. Rapid blood hyperoxygenation indicating "uncoupling" of blood flow and oxidative metabolism was followed by a return to basal levels over 3 min. Thus, initial nonoxidative glucose consumption during functional activation is gradually complemented by a slower adjustment of oxidative phosphorylation that "recouples" perfusion and oxygen consumption at a new equilibrium.

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Two children with hemimegalencephaly were examined by magnetic resonance imaging (MRI) and localized proton MR spectroscopy (MRS). In both cases, structural changes in the enlarged hemisphere included pachy- or polymicrogyria and gliosis of white matter. Associated metabolic disturbances included a dramatic reduction of glutamate and N-acetylaspartate (NAA) in white matter. Less severe or no alterations were noted in cortical gray matter, basal ganglia, and cerebellum. The older child (13 years) showed increased myoinositol in both gray and white matter as well as markedly increased choline-containing compounds in gray matter. Both children also had mildly decreased NAA levels in the white matter of the contralateral hemisphere. The spectroscopic findings indicate loss of vital neuroaxonal tissue and glial cell proliferation. Metabolic disturbances were more pronounced in the older child. The normal-appearing hemisphere was mildly affected in both cases.

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Functional mapping of human brain activation has been accomplished at high spatial and temporal resolution (voxel size 4.9 microliter, temporal increment 100 ms). The approach was based on oxygenation-sensitive long-echo time FLASH MRI sequences synchronized to multiply repeated cycles of visual stimulation in a CINE acquisition mode. This high temporal resolution revealed that stimulus-related signal intensity changes in human visual cortex display an initial latency followed by increases extending over several seconds. Furthermore, the temporal characteristics of the complete CINE MRI signal time course depended on the absolute and relative durations of activation and control periods and, for example, caused an apparent absence of a poststimulation "under-shoot" phenomenon. Complementing hyperoxygenation due to rapid hemodynamic adjustments, these results suggest signal intensity modulation by enhanced oxygen consumption and concomitant deoxygenation during prolonged and/or repetitive stimulation.

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