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

To examine the effect of acetazolamide, known to increase cerebral blood flow (CBF) and glyceryl trinitrate (GTN), known to increase cerebral blood volume (CBV) on the blood oxygenation level-dependent (BOLD) response in humans using 3 T magnetic resonance imaging (MRI), and to evaluate how pharmacological agents may modulate cerebral hemodynamic and thereby possibly the BOLD signal. Six subjects were randomly allocated to receive acetazolamide, GTN, or placebo in a double-blind three-way crossover controlled study. Before, during, and after drug administration we recorded the BOLD response during visual stimulation with reversing checkerboard. We found that acetazolamide caused significant depression of the BOLD response (P = 0.0066). The maximum decrease occurred at 5 minutes after infusion and was 51.9% (95% confidence interval [CI], 22.03-81.76). GTN did not influence the BOLD response (P = 0.55). The BOLD response is decreased during increased CBF by acetazolamide, suggesting an inverse relationship between global CBF and the BOLD response. GTN does not change the BOLD response. This indicates that GTN exerts an effect on the large vessels only and that CBV changes in the microvascular system are necessary to alter the BOLD response.

Cerebrovascular reactivity measured with arterial spin labeling and blood oxygen level dependent techniques

Paired pulse depression in the somatosensory cortex: Associations between MEG and BOLD fMRI

Frequency-dependent neural activity, CBF, and BOLD fMRI to somatosensory stimuli in isoflurane-anesthetized rats

The idea that regional cerebral blood flow (CBF) could reflect neuronal ­activity began with experiments of Roy and Sherrington in 1890.1 This concept is the basis for all hemodynamic-based brain imaging techniques being used today. The focal increase in CBF can be considered to relate directly to neuronal activity because the glucose metabolism and CBF changes are coupled closely.2 Thus, the measurement of CBF change induced by stimulation has been used for mapping brain functions. Because cerebral metabolic rate of glucose (CMRglu) and CBF changes are coupled, it is assumed that cerebral metabolic rate of oxygen (CMRO2) and CBF changes also are coupled. However, based on positron emission tomographic measurements of CBF and CMRO2 in humans during somatosensory and visual stimulation, Fox and colleagues reported that an increase in CBF surpassed an increase in CMRO2.3,4 Consequently, a mismatch between CBF and CMRO2 changes results in an increase in the capillary and venous oxygenation level, opening a new physiological parameter (in addition to CBF change) for brain mapping. In 1990, based on rat brain studies during global stimulation at 7 Tesla (T), Ogawa and colleagues at AT&T Bell Laboratories reported that functional brain mapping is possible by using the venous blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) contrast.5–7 The BOLD contrast relies on changes in deoxyhemoglobin (dHb), which acts as an endogenous paramagnetic contrast agent.5,8, Therefore, changes in the local dHb concentration in the brain lead to alterations in the signal intensity of magnetic resonance images.5–7,9

The most widely-used functional magnetic resonance imaging (fMRI) technique is based on the blood oxygenation level dependent (BOLD) effect, which requires at least partial uncoupling between cerebral blood flow (CBF) and oxygen consumption changes during increased mental activity. To compare BOLD and CBF effects during tasking, BOLD and flow-sensitive alternating inversion recovery (FAIR) images were acquired during visual stimulation with red goggles at a frequency of 8 Hz in an interleaved fashion. With the FAIR technique, absolute and relative CBF changes were determined. Relative oxygen consumption changes can be estimated using the BOLD and relative CBF changes. In gray matter areas in the visual cortex, absolute and relative CBF changes in humans during photic stimulation were 31 +/- 11 SD ml/100 g tissue/min and 43 +/- 16 SD % (n = 12), respectively, while the relative oxygen consumption change was close to zero. These findings agree extremely well with previous results using positron emission tomography. The BOLD signal change is not linearly correlated with the relative CBF increase across subjects and negatively correlates with the oxygen consumption change. Caution should be exercised when interpreting the BOLD percent change as a quantitative index of the CBF change, especially in inter-subject comparisons.

In simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), increased neuronal activity from epileptiform spikes commonly elicits positive blood oxygenation level-dependent (BOLD) responses. Negative responses are also occasionally seen and have not been explained. Recent studies describe BOLD signal changes before focal EEG spikes. We aimed to systematically study if the undershoot of a preceding positive response might explain the negative BOLD seen in the focus. Eighty-two patients with focal epilepsy who underwent EEG-fMRI at 3T were retrospectively studied. Studies with a focal negative BOLD response in the region of the spike field were reanalyzed using models with hemodynamic response functions (HRFs) peaking from -9 to +9 s around the spike. Eight patients met the inclusion criteria, showing negative BOLD responses in the spike field on standard analysis. None had positive BOLD responses immediately adjacent to the areas of deactivation. Regions of deactivation were found to have congruent preceding positive responses in two cases. These early activations were seen at the combined maps of -5 to -9 s. This study indicates that in a small proportion of patients with focal epilepsy in whom the standard analysis reveals focal negative responses, an earlier positive BOLD response is probably the cause. The origin of negative BOLD signal changes in the focus as a result of an epileptic event remains, however, unexplained in most of the patients in whom it occurs.

How reliable are fMRI–EEG studies of epilepsy? A nonparametric approach to analysis validation and optimization

The effects of APOE-ε4 on the BOLD response

Functional MR imaging was performed in sixteen healthy human subjects measuring both regional cerebral blood flow (CBF) and blood oxygen level dependent (BOLD) signal when visual and auditory stimuli were presented to subjects in the presence or absence of anesthesia. During anesthesia, 0.25 mean alveolar concentration (MAC) sevoflurane was administrated. We found that low-dose sevoflurane decreased the task-induced changes in both BOLD and CBF. Within the visual and auditory regions of interest inspected, both baseline CBF and the task-induced changes in CBF decreased significantly during anesthesia. Low-dose sevoflurane significantly altered the task-induced CBF-BOLD coupling; for a unit change of CBF, a larger change in BOLD was observed in the anesthesia condition than in the anesthesia-free condition. Low-dose sevoflurane was also found to have significant impact on the spatial nonuniformity of the task-induced coupling. The alteration of task-induced CBF-BOLD coupling by low-dose sevoflurane introduces ambiguity to the direct interpretation of functional MRI (fMRI) data based on only one of the indirect measures-CBF or BOLD. Our observations also indicate that the manipulation of the brain with an anesthetic agent complicates the model-based quantitative interpretation of fMRI data, in which the relative task-induced changes in oxidative metabolism are calculated by means of a calibrated model given the relative changes in the indirect vascular measures, usually CBF and BOLD.

Characteristic profiles of high gamma activity and blood oxygenation level-dependent responses in various language areas

Discrepancies between BOLD and flow dynamics in primary and supplementary motor areas: application of the balloon model to the interpretation of BOLD transients

Crowding, the inability to recognize an individual object in clutter (Bouma H. Nature 226: 177-178, 1970), is considered a major impediment to object recognition in peripheral vision. Despite its significance, the cortical loci of crowding are not well understood. In particular, the role of the primary visual cortex (V1) remains unclear. Here we utilize a diagnostic feature of crowding to identify the earliest cortical locus of crowding. Controlling for other factors, radially arranged flankers induce more crowding than tangentially arranged ones (Toet A, Levi DM. Vision Res 32: 1349-1357, 1992). We used functional magnetic resonance imaging (fMRI) to measure the change in mean blood oxygenation level-dependent (BOLD) response due to the addition of a middle letter between a pair of radially or tangentially arranged flankers. Consistent with the previous finding that crowding is associated with a reduced BOLD response [Millin R, Arman AC, Chung ST, Tjan BS. Cereb Cortex (July 5, 2013). doi:10.1093/cercor/bht159], we found that the BOLD signal evoked by the middle letter depended on the arrangement of the flankers: less BOLD response was associated with adding the middle letter between radially arranged flankers compared with adding it between tangentially arranged flankers. This anisotropy in BOLD response was present as early as V1 and remained significant in downstream areas. The effect was observed while subjects' attention was diverted away from the testing stimuli. Contrast detection threshold for the middle letter was unaffected by flanker arrangement, ruling out surround suppression of contrast response as a major factor in the observed BOLD anisotropy. Our findings support the view that V1 contributes to crowding.

The current functional state of local neuronal circuits controls the magnitude of a BOLD response to incoming stimuli

Regulation of cerebral blood flow (CBF) during hypoglycemia (HYPO) is critical for maintaining adequate glucose delivery to the brain; however, specific changes in regional CBF during HYPO are not well defined. We measured CBF in 14 T1DM (mean ± SD age 31 ± 7 yrs, DM duration 16 ± 5 yrs, A1c 7.2 ± 1.0 %) and 13 healthy controls (CON; age 35 ± 11 yrs, A1c 5.2 ± 0.5 %) using 3.0 T MRI continuous arterial spin labeling during fasting baseline (BAS), a hyperinsulinemic (2 mU/kg/min) euglycemic clamp (EUG; 90 mg/dl), followed by a hypoglycemic clamp (HYPO; 50 mg/dl). Global and regional changes in CBF were measured in 15 regions of interest (ROI). At BAS, gray matter CBF was similar in CON and T1DM (58 ± 16 vs. 61 ± 11 ml/100 gm brain/min). No significant changes in CBF were observed from BAS to EUG in any brain region in either CON or T1DM. However, during HYPO in T1DM, CBF increased by 10% in gray matter and 16% in brainstem, both p <0.05. CBF also increased by 10% - 18% in specific ROIs involved in awareness of internal states, reward and emotion (orbitofrontal cortex, insula, anterior cingulate cortex, thalamus, and substantia nigra; p<0.01 to p<0.05). Minimal increases in CBF (1% - 6%) were observed in regions primarily involved in sensory or motor function, (occipital cortex, motor cortex, cerebellum, caudate, putamen) or in the posterior cingulate (all p > 0.30). In CON, no significant global or regional changes in CBF occurred during HYPO. In all subjects, higher A1c correlated with greater increases in CBF during HYPO (p<0.05). Conclusions: 1) Hyperinsulinemia per se does not alter CBF in T1DM or CON, 2) During HYPO, brain blood flow increases more in T1DM vs. CON, especially in regions involved in integration of internal awareness, reward and emotion, compared to sensory or motor function, and 3) Greater increases in CBF in subjects with higher A1c suggest that compensatory physiologic mechanisms enable subjects with chronic exposure to hyperglycemia to maintain adequate cerebral glucose supply when plasma glucose levels are suddenly reduced. Disclosure D. C. Simonson: Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. N. R. Bolo: None. J. Theberge: None. G. Musen: None. A. M. Jacobson: None. Funding National Institutes of Health (DK073843)