Gradient-echo Blood Oxygenation Level Dependent Research Articles

Evaluation of T2-prepared blood oxygenation level dependent functional magnetic resonance imaging with an event-related task: Hemodynamic response function and reproducibility.

T2-prepared (T2prep) blood oxygenation level dependent (BOLD) functional MRI (fMRI) is an alternative fMRI approach developed to mitigate the susceptibility artifacts that are typically observed in brain regions near air-filled cavities, bleeding and calcification, and metallic objects in echo-planar-imaging (EPI) based fMRI images. Here, T2prep BOLD fMRI was evaluated in an event-related paradigm for the first time. Functional experiments were performed using gradient-echo (GRE) EPI, spin-echo (SE) EPI, and T2prep BOLD fMRI during an event-related visual task in 10 healthy human subjects. Each fMRI method was performed with a low (3.4 × 3.4 × 4 mm3) and a high (1.5 mm isotropic) spatial resolution on 3T and a high resolution (1.5 mm isotropic) on 7T. Robust activation were detected in the visual cortex with all three fMRI methods. In each group of fMRI scans (3T low resolution, 3T high resolution, and 7T high resolution), GRE EPI showed the highest signal change (ΔS/S), largest full-width-at-half-maximum (FWHM) and longest time-to-peak (TTP) extracted from the hemodynamic response functions (HRF), indicating substantial signal contribution from large draining veins which have longer response times than microvessels. In contrast, T2prep BOLD showed the lowest ΔS/S, smallest FWHM, and shortest TTP, suggesting that T2prep BOLD may have a purer T2-weighted BOLD contrast that is more sensitive to microvessels compared to GRE/SE EPI BOLD. This trend was more obvious in fMRI scans performed with a lower spatial resolution on a lower field (3T with a 3.4 × 3.4 × 4 mm3 voxel). Scan-rescan reproducibility in the same subjects was comparable among the three fMRI methods. The results from the current study are expected to be useful to establish T2prep BOLD as a useful alternative fMRI approach for event-related fMRI in brain regions with large susceptibility artifacts.

Improved laminar specificity and sensitivity by combining SE and GE BOLD signals

The most widely used gradient-echo (GE) blood oxygenation level-dependent (BOLD) contrast has high sensitivity, but low specificity due to draining vein contributions, while spin-echo (SE) BOLD approach at ultra-high magnetic fields is highly specific to neural active sites but has lower sensitivity. To obtain high specificity and sensitivity, we propose to utilize a vessel-size-sensitive filter to the GE-BOLD signal, which suppresses macrovascular contributions and to combine selectively retained microvascular GE-BOLD signals with the SE-BOLD signals. To investigate our proposed idea, fMRI with 0.8 mm isotropic resolution was performed on the primary motor and sensory cortices in humans at 7 T by implementing spin- and gradient-echo (SAGE) echo planar imaging (EPI) acquisition. Microvascular-passed sigmoidal filters were designed based upon the vessel-size-sensitive ΔR2*/ΔR2 value for retaining GE-BOLD signals originating from venous vessels with ≤ 45 μm and ≤ 65 μm diameter. Unlike GE-BOLD fMRI, the laminar profile of SAGE-BOLD fMRI with the vessel-size-sensitive filter peaked at ∼ 1.0 mm from the surface of the primary motor and sensory cortices, demonstrating an improvement of laminar specificity over GE-BOLD fMRI. Also, the functional sensitivity of SAGE BOLD at middle layers (0.75–1.5 mm) was improved by ∼ 80% to ∼100% when compared with SE BOLD. In summary, we showed that combined GE- and SE-BOLD fMRI with the vessel-size-sensitive filter indeed yielded improved laminar specificity and sensitivity and is therefore an excellent tool for high spatial resolution ultra-high filed (UHF)-fMRI studies for resolving mesoscopic functional units.

Modelling the depth-dependent VASO and BOLD responses in human primary visual cortex.

Functional magnetic resonance imaging (fMRI) using a blood-oxygenation-level-dependent (BOLD) contrast is a common method for studying human brain function noninvasively. Gradient-echo (GRE) BOLD is highly sensitive to the blood oxygenation change in blood vessels; however, the spatial signal specificity can be degraded due to signal leakage from activated lower layers to superficial layers in depth-dependent (also called laminar or layer-specific) fMRI. Alternatively, physiological variables such as cerebral blood volume using the VAscular-Space-Occupancy (VASO) contrast have shown higher spatial specificity compared to BOLD. To better understand the physiological mechanisms such as blood volume and oxygenation changes and to interpret the measured depth-dependent responses, models are needed which reflect vascular properties at this scale. For this purpose, we extended and modified the "cortical vascular model" previously developed to predict layer-specific BOLD signal changes in human primary visual cortex to also predict a layer-specific VASO response. To evaluate the model, we compared the predictions with experimental results of simultaneous VASO and BOLD measurements in a group of healthy participants. Fitting the model to our experimental data provided an estimate of CBV change in different vascular compartments upon neural activity. We found that stimulus-evoked CBV change mainly occurs in small arterioles, capillaries, and intracortical arteries and that the contribution from venules and ICVs is smaller. Our results confirm that VASO is less susceptible to large vessel effects compared to BOLD, as blood volume changes in intracortical arteries did not substantially affect the resulting depth-dependent VASO profiles, whereas depth-dependent BOLD profiles showed a bias towards signal contributions from intracortical veins.

Laminar fMRI using T2-prepared multi-echo FLASH

Functional magnetic resonance imaging (fMRI) using blood oxygenation level dependent (BOLD) contrast at a sub-millimeter scale is a promising technique to probe neural activity at the level of cortical layers. While gradient echo (GRE) BOLD sequences exhibit the highest sensitivity, their signal is confounded by unspecific extravascular (EV) and intravascular (IV) effects of large intracortical ascending veins and pial veins leading to a downstream blurring effect of local signal changes. In contrast, spin echo (SE) fMRI promises higher specificity towards signal changes near the microvascular compartment. However, the T2-weighted signal is typically sampled with a gradient echo readout imposing additional T2’-weighting.In this work, we used a T2-prepared (T2-prep) sequence with short GRE readouts to investigate its capability to acquire laminar fMRI data during a visual task in humans at 7 T. By varying the T2-prep echo time (TEprep) and acquiring multiple gradient echoes (TEGRE) per excitation, we studied the specificity of the sequence and the influence of possible confounding contributions to the shape of laminar fMRI profiles. By fitting and extrapolating the multi-echo GRE data to a TEGRE = 0 ms condition, we show for the first time laminar profiles free of T2’-pollution, confined to gray matter. This finding is independent of TEprep, except for the shortest one (31 ms) where hints of a remaining intravascular component can be seen. For TEGRE > 0 ms a prominent peak at the pial surface is observed that increases with longer TEGRE and dominates the shape of the profiles independent of the amount of T2-weighting. Simulations show that the peak at the pial surface is a result of static EV dephasing around pial vessels in CSF visible in GM due to partial voluming. Additionally, another, weaker, static dephasing effect is observed throughout all layers of the cortex, which is particularly obvious in the data with shortest T2-prep echo time. Our simulations show that this cannot be explained by intravascular dephasing but that it is likely caused by extravascular effects of the intracortical and pial veins. We conclude that even for TEGRE as short as 2.3 ms, the T2’-weighting added to the T2-weighting is enough to dramatically affect the laminar specificity of the BOLD signal change. However, the bulk of this corruption stems from CSF partial volume effects which can in principle be addressed by increasing the spatial resolution of the acquisition.

Validating Linear Systems Analysis for Laminar fMRI: Temporal Additivity for Stimulus Duration Manipulations

Advancements in ultra-high field (7 T and higher) magnetic resonance imaging (MRI) scanners have made it possible to investigate both the structure and function of the human brain at a sub-millimeter scale. As neuronal feedforward and feedback information arrives in different layers, sub-millimeter functional MRI has the potential to uncover information processing between cortical micro-circuits across cortical depth, i.e. laminar fMRI. For nearly all conventional fMRI analyses, the main assumption is that the relationship between local neuronal activity and the blood oxygenation level dependent (BOLD) signal adheres to the principles of linear systems theory. For laminar fMRI, however, directional blood pooling across cortical depth stemming from the anatomy of the cortical vasculature, potentially violates these linear system assumptions, thereby complicating analysis and interpretation. Here we assess whether the temporal additivity requirement of linear systems theory holds for laminar fMRI. We measured responses elicited by viewing stimuli presented for different durations and evaluated how well the responses to shorter durations predicted those elicited by longer durations. We find that BOLD response predictions are consistently good predictors for observed responses, across all cortical depths, and in all measured visual field maps (V1, V2, and V3). Our results suggest that the temporal additivity assumption for linear systems theory holds for laminar fMRI. We thus show that the temporal additivity assumption holds across cortical depth for sub-millimeter gradient-echo BOLD fMRI in early visual cortex.

Linear systems analysis for laminar fMRI: Evaluating BOLD amplitude scaling for luminance contrast manipulations

A fundamental assumption of nearly all functional magnetic resonance imaging (fMRI) analyses is that the relationship between local neuronal activity and the blood oxygenation level dependent (BOLD) signal can be described as following linear systems theory. With the advent of ultra-high field (7T and higher) MRI scanners, it has become possible to perform sub-millimeter resolution fMRI in humans. A novel and promising application of sub-millimeter fMRI is measuring responses across cortical depth, i.e. laminar imaging. However, the cortical vasculature and associated directional blood pooling towards the pial surface strongly influence the cortical depth-dependent BOLD signal, particularly for gradient-echo BOLD. This directional pooling may potentially affect BOLD linearity across cortical depth. Here we assess whether the amplitude scaling assumption for linear systems theory holds across cortical depth. For this, we use stimuli with different luminance contrasts to elicit different BOLD response amplitudes. We find that BOLD amplitude across cortical depth scales with luminance contrast, and that this scaling is identical across cortical depth. Although nonlinearities may be present for different stimulus configurations and acquisition protocols, our results suggest that the amplitude scaling assumption for linear systems theory across cortical depth holds for luminance contrast manipulations in sub-millimeter laminar BOLD fMRI.

Functional cerebral blood volume mapping with simultaneous multi-slice acquisition

The aim of this study is to overcome the current limits of brain coverage available with multi-slice echo planar imaging (EPI) for vascular space occupancy (VASO) mapping. By incorporating simultaneous multi-slice (SMS) EPI image acquisition into slice-saturation slab-inversion VASO (SS-SI VASO), many more slices can be acquired for non-invasive functional measurements of blood volume responses.Blood-volume-weighted VASO and gradient echo blood oxygenation level-dependent (GE-BOLD) data were acquired in humans at 7T with a 32-channel head coil. SMS-VASO was applied in three scenarios: A) high-resolution acquisition of spatially distant brain areas in the visuo-motor network (V1/V5/M1/S1); B) high-resolution acquisition of an imaging slab covering the entire M1/S1 hand regions; and C) low-resolution acquisition with near whole-brain coverage.The results show that the SMS-VASO sequence provided images enabling robust detection of blood volume changes in up to 20 slices with signal readout durations shorter than 150ms. High-resolution application of SMS-VASO revealed improved specificity of VASO to GM tissue without contamination from large draining veins compared to GE-BOLD in the visual cortex and in the sensory-motor cortex.It is concluded that VASO fMRI with SMS-EPI allows obtaining a reasonable three-dimensional coverage not achievable with standard VASO during the short time period when blood magnetization is approximately nulled. Due to the increased brain coverage and better spatial specificity to GM tissue of VASO compared to GE-BOLD signal, the proposed method may play an important role in high-resolution human fMRI at 7T.

Quantitative in vivo 23Na MR imaging of the healthy human kidney: determination of physiological ranges at 3.0T with comparison to DWI and BOLD

The purpose of this prospective study was to assess the normal physiologic ranges of the renal corticomedullary 23Na-concentration ([23Na]) gradient at 3.0T in healthy volunteers. The corticomedullary [23Na] gradient was correlated with other functional MR imaging parameters--blood oxygenation level dependent (BOLD) and diffusion-weighted imaging (DWI)--and to individual and physiologic parameters--age, gender, estimated glomerular filtration rate (eGFR), body mass index (BMI), and blood serum sodium concentration ([23Na]serum). 50 healthy volunteers (30 m, 20 w; mean age: 29.2 years) were included in this IRB-approved study, without a specific a priori preparation in regard to water or food intake. For 23Na-imaging a 3D density adapted, radial gradient echo (GRE)-sequence (spatial resolution=5×5×5 mm3) was used in combination with a dedicated 23Na-coil and 23Na-reference phantoms. [23Na] values of the corticomedullary [23Na] gradient were measured by placement of a linear region of interest (20×1 mm2) from the renal cortex in the direction of the renal medulla. By using external standard reference phantoms, [23Na] was calculated in mmol/L of wet tissue volume (mmol/l WTV). Axial diffusion-weighted images (spatial resolution=1.7×1.7×5.0 mm3) and 2D GRE BOLD images (spatial resolution=1.2×1.2×4.0 mm3) were acquired. Mean values±standard deviations for [23Na], apparent diffusion coefficient (ADC) values, and R2* values were computed for each volunteer. The corticomedullary 23Na-concentration gradient (in mmol/l/mm) was calculated along the area of linear concentration increase from the cortex in the direction of the medulla. Correlations between the [23Na] and DWI, BOLD, and the physiologic parameters were assessed with Pearson correlation coefficients. The mean corticomedullary [23Na] for all healthy volunteers increased from the renal cortex (58±17 mmol/l WTV) in the direction of the medulla (99±18 mmol/l WTV). The inter-individual differences ranged from respective cortical and medullary values of 27 and 63 mmol/L WTV to 126 and 187 mmol/L WTV. No statistically significant differences in renal [23Na] were found based on differences in individual or physiologic parameters (age, gender, [23Na]serum, BMI, GFR). No ADC or R2* gradients were identified, and [23Na] did not correlate with these parameters. Renal corticomedullary [23Na] values increase from the cortex in the direction of the medullary pyramid, demonstrating wide inter-individual ranges and no significant correlations with age, gender, [23Na]serum, BMI, GFR, ADC, or R2* values. For future clinical evaluations, an approach relying on renal stimulation (e.g. pharmacologically induced diuresis) may be applicable to account for wide inter-individual ranges of normal [23Na].

Echo-Time and Field Strength Dependence of BOLD Reactivity in Veins and Parenchyma Using Flow-Normalized Hypercapnic Manipulation

While the BOLD (Blood Oxygenation Level Dependent) contrast mechanism has demonstrated excellent sensitivity to neuronal activation, its specificity with regards to differentiating vascular and parenchymal responses has been an area of ongoing concern. By inducing a global increase in Cerebral Blood Flow (CBF), we examined the effect of magnetic field strength and echo-time (TE) on the gradient-echo BOLD response in areas of cortical gray matter and in resolvable veins. In order to define a quantitative index of BOLD reactivity, we measured the percent BOLD response per unit fractional change in global gray matter CBF induced by inhaling carbon dioxide (CO2). By normalizing the BOLD response to the underlying CBF change and determining the BOLD response as a function of TE, we calculated the change in R2 * (ΔR2 *) per unit fractional flow change; the Flow Relaxation Coefficient, (FRC) for 3T and 1.5T in parenchymal and large vein compartments. The FRC in parenchymal voxels was 1.76±0.54 fold higher at 3T than at 1.5T and was 2.96±0.66 and 3.12±0.76 fold higher for veins than parenchyma at 1.5T and 3T respectively, showing a quantitative measure of the increase in specificity to parenchymal sources at 3T compared to 1.5T. Additionally, the results allow optimization of the TE to prioritize either maximum parenchymal BOLD response or maximum parenchymal specificity. Parenchymal signals peaked at TE values of 62.0±11.5 ms and 41.5±7.5 ms for 1.5T and 3T, respectively, while the response in the major veins peaked at shorter TE values; 41.0±6.9 ms and 21.5±1.0 ms for 1.5T and 3T. These experiments showed that at 3T, the BOLD CNR in parenchymal voxels exceeded that of 1.5T by a factor of 1.9±0.4 at the optimal TE for each field.

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.

Blood oxygenation level‐dependent (BOLD) total and extravascular signal changes and ΔR2* in human visual cortex at 1.5, 3.0 and 7.0 T

The characterisation of the extravascular (EV) contribution to the blood oxygenation level-dependent (BOLD) effect is important for understanding the spatial specificity of BOLD contrast and for modelling approaches that aim to extract quantitative metabolic parameters from the BOLD signal. Using bipolar crusher gradients, total (b = 0 s/mm(2) ) and predominantly EV (b = 100 s/mm(2) ) gradient echo BOLD ΔR(2)* and signal changes (ΔS/S) in response to visual stimulation (flashing checkerboard; f = 8 Hz) were investigated sequentially (within < 3 h) at 1.5, 3.0 and 7.0 T in the same subgroup of healthy volunteers (n = 7) and at identical spatial resolutions (3.5 × 3.5 × 3.5 mm(3)). Total ΔR(2)* (z-score analysis) values were -0.61 ± 0.10 s(-1) (1.5 T), -0.74 ± 0.05 s(-1) (3.0 T) and -1.37 ± 0.12 s(-1) (7.0 T), whereas EV ΔR(2)* values were -0.28 ± 0.07 s(-1) (1.5 T), -0.52 ± 0.07 s(-1) (3.0 T) and -1.25 ± 0.11 s(-1) (7.0 T). Although EV ΔR(2)* increased linearly with field, as expected, it was found that EV ΔS/S increased less than linearly with field in a manner that varied with TE choice. Furthermore, unlike ΔR(2)*, total and EV ΔS/S did not converge at 7.0 T. These trends were similar whether a z-score analysis or occipital lobe-based region-of-interest approach was used for voxel selection. These findings suggest that calibrated BOLD approaches may benefit from an EV ΔR(2)* measurement as opposed to a ΔS/S measurement at a single TE.

Retinotopic mapping with spin echo BOLD at 7T

For blood oxygenation level-dependent (BOLD) functional MRI experiments, contrast-to-noise ratio (CNR) increases with increasing field strength for both gradient echo (GE) and spin echo (SE) BOLD techniques. However, susceptibility artifacts and nonuniform coil sensitivity profiles complicate large field-of-view fMRI experiments (e.g., experiments covering multiple visual areas instead of focusing on a single cortical region). Here, we use SE BOLD to acquire retinotopic mapping data in early visual areas, testing the feasibility of SE BOLD experiments spanning multiple cortical areas at 7T. We also use a recently developed method for normalizing signal intensity in T 1-weighted anatomical images to enable automated segmentation of the cortical gray matter for scans acquired at 7T with either surface or volume coils. We find that the CNR of the 7T GE data (average single-voxel, single-scan stimulus coherence: 0.41) is almost twice that of the 3T GE BOLD data (average coherence: 0.25), with the CNR of the SE BOLD data (average coherence: 0.23) comparable to that of the 3T GE data. Repeated measurements in individual subjects find that maps acquired with 1.8-mm resolution at 3T and 7T with GE BOLD and at 7T with SE BOLD show no systematic differences in either the area or the boundary locations for V1, V2 and V3, demonstrating the feasibility of high-resolution SE BOLD experiments with good sensitivity throughout multiple visual areas.

Simultaneous acquisition of gradient echo/spin echo BOLD and perfusion with a separate labeling coil

Arterial spin labeling-based cerebral blood flow imaging complements blood oxygenation level dependent (BOLD) imaging with a measure that is more quantitative and has better specificity to neuronal activation. Relative to gradient echo BOLD, spin echo BOLD has better spatial specificity because it is less biased to large draining veins. Although there have been many studies comparing simultaneously acquired cerebral blood flow data with gradient echo BOLD data in fMRI, there have been few studies comparing cerebral blood flow with SE BOLD and no study comparing all three. We present a pulse sequence that simultaneously acquires cerebral blood flow data with a separate labeling coil, gradient echo BOLD, and spin echo BOLD images. Simultaneous acquisition avoids interscan variability, allowing more direct assessment and comparison of each contrast's relative specificity and reproducibility. Furthermore, it facilitates studies that may benefit from multiple complementary measures.

BOLD‐specific cerebral blood volume and blood flow changes during neuronal activation in humans

To understand and predict the blood-oxygenation level-dependent (BOLD) fMRI signal, an accurate knowledge of the relationship between cerebral blood flow (DeltaCBF) and volume (DeltaCBV) changes is critical. Currently, this relationship is widely assumed to be characterized by Grubb's power-law, derived from primate data, where the power coefficient (alpha) was found to be 0.38. The validity of this general formulation has been examined previously, and an alpha of 0.38 has been frequently cited when calculating the cerebral oxygen metabolism change (DeltaCMRo(2)) using calibrated BOLD. However, the direct use of this relationship has been the subject of some debate, since it is well established that the BOLD signal is primarily modulated by changes in 'venous' CBV (DeltaCBV(v), comprising deoxygenated blood in the capillary, venular, and to a lesser extent, in the arteriolar compartments) instead of total CBV, and yet DeltaCBV(v) measurements in humans have been extremely scarce. In this work, we demonstrate reproducible DeltaCBV(v) measurements at 3 T using venous refocusing for the volume estimation (VERVE) technique, and report on steady-state DeltaCBV(v) and DeltaCBF measurements in human subjects undergoing graded visual and sensorimotor stimulation. We found that: (1) a BOLD-specific flow-volume power-law relationship is described by alpha = 0.23 +/- 0.05, significantly lower than Grubb's constant of 0.38 for total CBV; (2) this power-law constant was not found to vary significantly between the visual and sensorimotor areas; and (3) the use of Grubb's value of 0.38 in gradient-echo BOLD modeling results in an underestimation of DeltaCMRo(2).

Pain fMRI in rat cervical spinal cord: An echo planar imaging evaluation of sensitivity of BOLD and blood volume-weighted fMRI

Objective measure of pain is valuable in drug discovery research and development of analgesics. Spinal cord is an important relay of the pain pathway, and fMRI offers an excellent opportunity to quantify pain using activation in the spinal cord induced by painful stimuli. fMRI literature of cervical spinal cord with regard to the spatial extent, in both longitudinal and cross-sectional directions, of neuronal activation induced by noxious stimulation is ambiguous. This study investigates the feasibility of developing a robust pain assay using fMRI in the cervical spinal cord in α-chloralose anesthetized rats subjected to transcutaneous noxious electrical stimulation of the forepaw. Blood oxygenation level dependent (BOLD) and blood volume (BV)-weighted fMRI data were acquired without and with intravenous injection of ultra small superparamagnetic iron oxide particles (USPIO), respectively. BOLD data were acquired by gradient-echo (GE) and spin-echo (SE) echo planar imaging (EPI), while BV-weighted fMRI data were acquired only by GE EPI. Cervical spinal cord activity was robustly detected by all three fMRI techniques. The sensitivity of the fMRI signal was highest in GE BV-weighted fMRI followed in order by GE BOLD, and SE BOLD, respectively. Spatially, the fMRI signal extended ∼ 9 mm in the longitudinal direction, covering C 4–C 8 segments, coinciding with the synapse location of afferent terminals from the stimulated site. In the cross-sectional direction, the signal change is localized predominantly to the ipsilateral dorsal region. This study demonstrates that cervical spinal cord fMRI can be performed reliably in anesthetized rats offering it as a potential tool for analgesic drug development.

Investigating the source of BOLD nonlinearity in human visual cortex in response to paired visual stimuli

Several studies have demonstrated significant nonlinearity in the blood-oxygenation-level-dependent (BOLD) signal. Completely understanding the nature of this nonlinear behavior is important in the interpretation of the BOLD signal. However, this task is hindered by the uncertainty of the source of BOLD nonlinearity which could come from neuronal and/or vascular origin. The obscurity of this issue not only impedes accurate modeling of BOLD nonlinearity, but also limits generalization of the conclusions regarding BOLD nonlinearity. To examine this issue, we eliminated nonlinear contributions from the neuronal response and selectively study BOLD nonlinearity under only the vascular effect by employing a paired-stimulus paradigm composed of two ultra-short visual stimuli separated by a variable inter-stimulus interval (ISI). ISIs chosen were long enough (≥ 1s) to ensure invariant neuronal activity to all stimuli. Under this circumstance, we still observed significant nonlinearity in the BOLD signal reflected by a progressive recovery of BOLD response to the second stimuli as ISI gets longer and delayed BOLD onset latency. These nonlinear behaviors identified in the BOLD signal originate entirely from the vascular responses as the neuronal responses to all stimuli are identical. More importantly, we found that BOLD nonlinearity became much less significant after we removed activated pixels from large vessels. These finds reveal that the dominant component, if not all, of the source of BOLD nonlinearity comes from large-vessel hemodynamic response. They also suggest a possible mechanism to improve the spatial specificity of gradient-echo BOLD signal for fMRI mapping based on the characteristics of vascular refractoriness.

Oxygenation and hematocrit dependence of transverse relaxation rates of blood at 3T

Knowledge of the transverse relaxation rates R2 and R2* of blood is relevant for quantitative assessment of functional MRI (fMRI) results, including calibration of blood oxygenation and measurement of tissue oxygen extraction fractions (OEFs). In a temperature controlled circulation system, these rates were measured for blood in vitro at 3T under conditions akin to the physiological state. Single spin echo (SE) and gradient echo (GRE) sequences were used to determine R2 and R2*, respectively. Both rates varied quadratically with deoxygenation, and changes in R2* were found to be due predominantly to changes in R2. These data were used to estimate intravascular blood oxygenation level dependent (BOLD) contributions during visual activation. Due to the large R2* in venous blood, intravascular SE BOLD signal changes were larger than GRE effects at echo times above 30 ms. When including extravascular effects to estimate the total BOLD effect, GRE BOLD dominated due to the large tissue volume fraction.

Neural Interpretation of Blood Oxygenation Level-Dependent fMRI Maps at Submillimeter Columnar Resolution

Whether conventional gradient-echo (GE) blood oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is able to map submillimeter-scale functional columns remains debatable mainly because of the spatially nonspecific large vessel contribution, poor sensitivity and reproducibility, and lack of independent evaluation. Furthermore, if the results from optical imaging of intrinsic signals are directly applicable, regions with the highest BOLD signals may indicate neurally inactive domains rather than active columns when multiple columns are activated. To examine these issues, we performed BOLD fMRI at a magnetic field of 9.4 tesla to map orientation-selective columns of isoflurane-anesthetized cats. We could not convincingly map orientation columns using conventional block-design stimulation and differential analysis method because of large fluctuations of signals. However, we successfully obtained GE BOLD iso-orientation maps with high reproducibility (r = 0.74) using temporally encoded continuous cyclic orientation stimulation with Fourier data analysis, which reduces orientation-nonselective signals such as draining artifacts and is less sensitive to signal fluctuations. We further reduced large vessel contribution using the improved spin-echo (SE) BOLD method but with overall decreased sensitivity. Both GE and SE BOLD iso-orientation maps excluding large pial vascular regions were significantly correlated to maps with a known neural interpretation, which were obtained in contrast agent-aided cerebral blood volume fMRI and total hemoglobin-based optical imaging of intrinsic signals at a hemoglobin iso-sbestic point (570 nm). These results suggest that, unlike the expectation from deoxyhemoglobin-based optical imaging studies, the highest BOLD signals are localized to the sites of increased neural activity when column-nonselective signals are suppressed.

Sources of phase changes in BOLD and CBV‐weighted fMRI

Phase changes in blood oxygenation-level dependent (BOLD) fMRI have been observed in humans; however, their exact origin has not yet been fully elucidated. To investigate this issue, we acquired gradient-echo (GE) BOLD and cerebral blood volume (CBV)-weighted fMRI data in anesthetized cats during visual stimulation at 4.7T and 9.4T, before and after injection of a superparamagnetic contrast agent (monocrystalline iron oxide nanoparticles, MION), respectively. In BOLD fMRI, large positive changes in both magnitude and phase were observed predominantly in the cortical surface area, where the large draining veins reside. In CBV-weighted fMRI, large negative changes in both magnitude and phase were detected mainly in the middle cortical area, where the greatest CBV change takes place. Additionally, the phase change was temporally correlated with the magnitude response and was linearly dependent on the echo time (TE), which cannot be explained by the intravascular (IV) contribution and functional temperature change. Phase changes with the opposite polarity were also observed in the regions around the dominant phase changes. These phase changes can be explained by the application of the "Lorentz sphere" theory in the presence of relevant activation-induced changes in vessels. The volume-averaged magnetization and its demagnetization are the main sources of fMRI signal phase change.

Improved spatial localization of post-stimulus BOLD undershoot relative to positive BOLD

The negative blood oxygenation level-dependent (BOLD) signal following the cessation of stimulation (post-stimulus BOLD undershoot) is observed in functional magnetic resonance imaging (fMRI) studies. However, its spatial characteristics are unknown. To investigate this, gradient-echo BOLD fMRI in response to visual stimulus was obtained in isoflurane-anesthetized cats at 9.4 T. Since the middle cortical layer (layer 4) is known to have the highest metabolic and cerebral blood volume (CBV) responses, images were obtained to view the cortical cross-section. Robust post-stimulus BOLD undershoot was observed in all studies, and lasted longer than 30 s after the cessation of 40–60 s stimulation. The magnitude of post-stimulus BOLD undershoot was linearly dependent on echo time with little intercept when extrapolating to TE=0, indicating that the T2* change is the major cause of the BOLD undershoot. The post-stimulus BOLD undershoot was observed within the cortex and near the surface of the cortex, while the prolonged CBV elevation was observed only at the middle of the cortex. Within the cortex, the largest post-stimulus undershoot was detected at the middle of the cortex, similar to the CBV increase during the stimulation period. Our findings demonstrate that, even though there is significant contribution from pial vessel signals, the post-stimulus undershoot BOLD signal is useful to improve the spatial localization of fMRI to active cortical sites.