Seong-Gi Kim

Localized cerebral blood flow response at submillimeter columnar resolution

Functional magnetic resonance imaging (fMRI) has been widely used for imaging brain functions. However, the extent of the fMRI hemodynamic response around the active sites, at submillimeter resolution, remains poorly understood and controversial. With the use of perfusion-based fMRI, we evaluated the hemodynamic response in the cat visual cortex after orientation-specific stimuli. Activation maps obtained by using cerebral blood flow fMRI measurements were predominantly devoid of large draining vein contamination and reproducible at columnar resolution. Stimulus-specific cerebral blood flow responses were spatially localized to individual cortical columns, and columnar layouts were resolved. The periodic spacing of orientation columnar structures was estimated to be 1.1 ± 0.2 mm (n = 14 orientations, five animals), consistent with previous findings. The estimated cerebral blood flow response at full width at half-maximum was 470 μm under single-stimulus conditions without differential subtraction. These results suggest that hemodynamic-based fMRI can indeed be used to map individual functional columns if large-vessel contributions can be minimized or eliminated.

Determination of relative CMRO2 from CBF and BOLD changes: Significant increase of oxygen consumption rate during visual stimulation

The blood oxygenation level‐dependent (BOLD) effect in functional magnetic resonance imaging depends on at least partial uncoupling between cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) changes. By measuring CBF and BOLD simultaneously, the relative change in CMRO2 can be estimated during neural activity using a reference condition obtained with known CMRO2 change. In this work, nine subjects were studied at a magnetic field of 1.5 T; each subject underwent inhalation of a 5% carbon dioxide gas mixture as a reference and two visual stimulation studies. Relative CBF and BOLD signal changes were measured simultaneously using the flow‐sensitive alternating inversion recovery (FAIR) technique. During hypercapnia established by an end‐tidal CO2 increase of 1.46 kPa, CBF in the visual cortex increased by 47.3 ± 17.3% (meanu2009±u2009SD; nu2009=u20099), and ΔR*2 was −0.478 ± 0.147 sec−1, which corresponds to BOLD signal change of 2.4 ± 0.7% with a gradient echo time of 50 msec. During black/white visual stimulation reversing at 8 Hz, regional CBF increase in the visual cortex was 43.6 ± 9.4% (nu2009=u200918), and ΔR*2 was −0.114 ± 0.086 sec−1, corresponding to a BOLD signal change of 0.6 ± 0.4%. Assuming that CMRO2 does not change during hypercapnia and that hemodynamic responses during hypercapnia and neural stimulation are similar, relative CMRO2 change was determined using BOLD biophysical models. The average CMRO2 change in the visual cortex ranged from 15.6 ± 8.1% (nu2009=u200918) with significant cerebral blood volume (CBV) contribution to 29.6 ± 18.8% without significant CBV contribution. A weak positive correlation between CBF and CMRO2 changes was observed, suggesting the CMRO2 increase is proportional to the CBF increase. Magn Reson Med 41:1152–1161, 1999.

Simultaneous Blood Oxygenation Level-Dependent and Cerebral Blood Flow Functional Magnetic Resonance Imaging during Forepaw Stimulation in the Rat

The blood oxygenation level-dependent (BOLD) contrast mechanism can be modeled as a complex interplay between CBF, cerebral blood volume (CBV), and CMRO2. Positive BOLD signal changes are presumably caused by CBF changes in excess of increases in CMRO2. Because this uncoupling between CBF and CMRO2 may not always be present, the magnitude of BOLD changes may not be a good index of CBF changes. In this study, the relation between BOLD and CBF was investigated further. Continuous arterial spin labeling was combined with a single-shot, multislice echo-planar imaging to enable simultaneous measurements of BOLD and CBF changes in a well-established model of functional brain activation, the electrical forepaw stimulation of a-chloralose-anesthetized rats. The paradigm consisted of two 18- to 30-second stimulation periods separated by a 1-minute resting interval. Stimulation parameters were optimized by laser Doppler flowmetry. For the same cross-correlation threshold, the BOLD and CBF active maps were centered within the size of one pixel (470 µm). However, the BOLD map was significantly larger than the CBF map. Measurements taken from 15 rats at 9.4 T using a 10-millisecond echo-time showed 3.7 ± 1.7% BOLD and 125.67 ± 81.7% CBF increases in the contralateral somatosensory cortex during the first stimulation, and 2.6 ± 1.2% BOLD and 79.3 ± 43.6% CBF increases during the second stimulation. The correlation coefficient between BOLD and CBF changes was 0.89. The overall temporal correlation coefficient between BOLD and CBF time-courses was 0.97. These results show that under the experimental conditions of the current study, the BOLD signal changes follow the changes in CBF.

Spatiotemporal dynamics of the BOLD fMRI signals: Toward mapping submillimeter cortical columns using the early negative response

The existence of the early‐negative blood‐oxygenation‐level‐dependent (BOLD) response is controversial and its practical utility for mapping brain functions with columnar spatial specificity remains questionable. To address these issues, gradient‐echo BOLD fMRI studies were performed at 4.7 T and 9.4 T using the well‐established orientation column model in the cat visual cortex. A robust transient early‐negative BOLD response was consistently observed in anesthetized cat (‐0.35 ± 0.09%, mean ± SD, n = 8 at 2.9 ± 0.5 sec poststimulus onset for 4.7 T, TE = 31 ms; ‐0.29 ± 0.10%, n = 4 at 3.0 ± 0.8 sec poststimulus onset for 9.4 T, TE = 12 ms). In addition to its temporal evolution, the BOLD response also evolved dynamically in the spatial domain. The initially spatially localized early‐negative signal appeared to dynamically drain from the active sites toward large vessels, followed by a wave of the delayed positive signal, which exhibited similar spatiotemporal dynamics. Only the early‐negative BOLD response within 2 sec of the stimulus onset (not the entire dip) yielded columnar layouts without differential subtraction. The functional maps of two orthogonal orientations using the first 2‐sec dip were indeed complementary. On the other hand, the delayed positive BOLD response appeared diffused and extended beyond the active sites. It was thus less suitable to resolve columnar layouts. These results have implications for the design and interpretation of the BOLD fMRI at columnar resolution. Magn Reson Med 44:231–242, 2000.

Spatial and temporal limits in cognitive neuroimaging with fMRI

A large body of research in human perception and cognition has been concerned with the segregation of mental events into their presumed hierarchical processing stages, the temporal aspect of such processing being termed mental chronometry. Advances in single-event functional magnetic resonance imaging (fMRI) have allowed the extraction of relative timing information between the onset of activity in different neural substrates as well as the duration of cognitive processing during a task, offering new opportunities in the study of human perception and cognition. Single-event fMRI studies have also facilitated increased spatial resolution in fMRI, allowing studies of columnar organization in humans. Important processes such as object recognition, binocular vision and other processes are thought to be organized at the columnar level; thus, these advances in the spatial and temporal capabilities of fMRI allow a new generation of cognitive and basic neuroscience studies to be performed, investigating the temporal and spatial relationships between these cortical sub-units. Such experiments bear a closer resemblance to single-unit or evoked-potential studies than to classical static brain activation maps and might serve as a bridge between primate electrophysiology and human studies. These advances are initially demonstrated only in simple visual and motor system tasks and it is likely to be several years before the techniques we describe are robust enough for general use.

Quantitative relations between parietal activation and performance in mental rotation

The quantitative relationships between functional activation of the superior parietal lobule (SPL) and performance in the Shepard-Metzler mental rotation task were investigated in 16 human subjects using magnetic resonance (MR) imaging at high field (4 Tesla). Subjects were shown pairs of perspective drawings of three-dimensional objects and asked to judge whether they were the same or mirror images. Increased SPL activation was associated with a higher proportion of errors in performance. The increase in errors, and the concomitant increase in SPL activation, could be due to an increased difficulty in, and therefore increased demands for, information processing at several stages involved in making a decision, including encoding of the visual images shown, mentally rotating them, and judging whether they are the same or mirror images.

In Vivo Measurements of Brain Glucose Transport Using the Reversible Michaelis–Menten Model and Simultaneous Measurements of Cerebral Blood Flow Changes during Hypoglycemia:

Glucose is the major substrate that sustains normal brain function. When the brain glucose concentration approaches zero, glucose transport across the blood–brain barrier becomes rate limiting for metabolism during, for example, increased metabolic activity and hypoglycemia. Steady-state brain glucose concentrations in α-chloralose anesthetized rats were measured noninvasively as a function of plasma glucose. The relation between brain and plasma glucose was linear at 4.5 to 30 mmol/L plasma glucose, which is consistent with the reversible Michaelis–Menten model. When the model was fitted to the brain glucose measurements, the apparent Michaelis-Menten constant, Kt, was 3.3 ± 1.0 mmol/L, and the ratio of the maximal transport rate relative to CMRglc, Tmax/CMRglc, was 2.7 ± 0.1. This Kt is comparable to the authors previous human data, suggesting that glucose transport kinetics in humans and rats are similar. Cerebral blood flow (CBF) was simultaneously assessed and constant above 2 mmol/L plasma glucose at 73 ± 6 mL 100 g−1 min−1. Extrapolation of the reversible Michaelis–Menten model to hypoglycemia correctly predicted the plasma glucose concentration (2.1 ± 0.6 mmol/L) at which brain glucose concentrations approached zero. At this point, CBF increased sharply by 57% ± 22%, suggesting that brain glucose concentration is the signal that triggers defense mechanisms aimed at improving glucose delivery to the brain during hypoglycemia.

Reproducibility of BOLD-Based Functional MRI Obtained at 4 T

The reproducibility of activation patterns in the whole brain obtained by functional magnetic resonance imaging (fMRI) experiments at 4 Tesla was studied with a simple finger‐opposition task. Six subjects performed three runs in one session, and each run was analyzed separately with the t‐test as a univariate method and Fishers linear discriminant analysis as a multivariate method. Detrending with a first‐ and third‐order polynomial as well as logarithmic transformation as preprocessing steps for the t‐test were tested for their impact on reproducibility. Reproducibility across the whole brain was studied by using scatter plots of statistical values and calculating the correlation coefficient between pairs of activation maps. In order to compare reproducibility of “activated” voxels across runs, subjects and models, 2% of all voxels in the brain with the highest statistical values were classified as activated. The analysis of reproducible activated voxels was performed for the whole brain and within regions of interest. We found considerable variability in reproducibility across subjects, regions of interest, and analysis methods. The t‐test on the linear detrended data yielded better reproducibility than Fishers linear discriminant analysis, and therefore seems to be a robust although conservative method. Preliminary data indicate that these modeling results may be reversed by preprocessing to reduce respiratory and cardiac physiological noise effects. The reproducibility of both the position and number of activated voxels in the sensorimotor cortex was highest, while that of the supplementary motor area was much lower, with reproducibility of the cerebellum falling in between the other two areas. Hum. Brain Mapping 7:267–283, 1999.

Mental rotation studied by functional magnetic resonance imaging at high field (4 tesla): Performance and cortical activation

We studied the performance and cortical activation patterns during a mental rotation task (Shepard & Metzler, 1971) using functional magnetic resonance imaging (fMlU) at high field (4 Tesla). Twenty-four human subjects were imaged (fMRI group), whereas six additional subjects performed the task without being imaged (control group). All subjects were shown pairs of perspective drawings of 31, objects and asked to judge whether they were the same or mirror images. The measures of performance examined included (1) the percentage of errors, (2) the speed of performance, calculated as the inverse of the average response time, and (3) the rate of rotation for those object pairs correctly identified as same. We found the following: (1) Subjects in the fMRI group performed well outside and inside the magnet, and, in the latter case, before and during data acquisition. Moreover, performance over time improved in the same manner as in the control group. These findings indicate that exposure to high magnetic fields does not impair performance in mental rotation. (2) Functional activation data were analyzed from 16 subjects of the fMRI goup. Several cortical areas were activated during task performance. The relations between the measures of performance above and the magnitude of activation of specific cortical areas were investigated by anatomically demarcating these areas of interest and calculating a normalized activation for each one of them. (3) We used the multivariate technique of hierarchical tree modeling to determine functional clustering among areas of interest and performance measures. Two main branches were distinguished: One comprised areas in the right hemisphere and the extrastriate and superior parietal lobules bilaterally, whereas the other comprised areas of the left hemisphere and the frontal pole bilaterally; all three performance measures above clustered with the former branch. Specifically, performance outcome (percentage of errors) clustered with the parieto-occipital subcluster, whereas both the speed of performance and the rate of mental rotation clustered with the right precentral gyms. We conclude that the mental rotation paradigm used involves the cooperative interaction of functional groups of cortical areas of which some are probably more specifically associated with performance, whereas others may serve a more general function within the task constraints.

Cortical depth‐dependent gradient‐echo and spin‐echo BOLD fMRI at 9.4T

To examine cortical depth‐related spatial specificity and signal changes in gradient‐echo (GE) and spin‐echo (SE) blood oxygenation level‐dependent (BOLD) fMRI signals, a well‐established cat visual stimulation model was used at 9.4T. The GE BOLD signal percent change is the highest at the surface of the cortex containing pial vessels, and decreases as cortical depth increases. In contrast, the SE BOLD signal is more specific to parenchyma, showing the highest signal change in the middle cortical areas. The stimulation‐induced ΔR u20092* to ΔR2 ratio is dependent on the vessel size, which is related to basal susceptibility effects. The averaged ratio of ΔR u20092* to ΔR2 in all active regions, including large vessels, is 3.3 ± 0.5 (N = 6). The averaged ratio of ΔR u20092* to ΔR2 is 8.8 ± 1.7 (N = 4) on the surface of the cortex with large pial draining vessels, and decreases to 1.9 ± 0.1 on the middle cortical areas with parenchymal microvessels. ΔR u20092* /ΔR2 is closely related to basal susceptibility effects and can be used to differentiate tissue from vessel regions. Magn Reson Med 51:518–524, 2004.