Quantitative magnetic resonance imaging (MRI) and spectroscopy (MRS) measurements of energy metabolism (i.e. cerebral metabolic rate of oxygen consumption, CMR O2 ), blood circulation (i.e. cerebral blood flow, CBF, and volume, CBV), and functional MRI (fMRI) signal over a wide range of neuronal activity and pharmacological treatments are used to interpret the neurophysiologic basis of blood oxygenation level dependent (BOLD) image-contrast at 7 T in glutamatergic neurons of rat cerebral cortex. Multi-modal MRI and MRS measurements of CMR O2 , CBF, CBV and BOLD signal (both gradient-echo and spin-echo) are used to interpret the neuroenergetic basis of BOLD image-contrast. Since each parameter that can influence the BOLD image-contrast is measured quantitatively and separately, multi-modal measurements of changes in CMR O2 , CBF, CBV, BOLD fMRI signal allow calibration and validation of the BOLD image-contrast. Good agreement between changes in CMR O2 calculated from BOLD theory and measured by 13 C MRS, reveals that BOLD fMRI signal-changes at 7 T are closely linked with alterations in neuronal glucose oxidation, both for activation and deactivation paradigms. To determine the neurochemical basis of BOLD, pharmacological treatment with lamotrigine, which is a neuronal voltagedependent Na channel blocker and neurotransmitter glutamate release inhibitor, is used in a rat forepaw stimulation model. Attenuation of the functional changes in CBF and BOLD with lamotrigine reveals that the fMRI signal is associated with release of glutamate from neurons, which is consistent with a link between neurotransmitter cycling and energy metabolism. Comparisons of CMR O2 and CBF over a wide dynamic range of neuronal activity provide insight into the regulation of energy metabolism and oxygen delivery in the cerebral cortex. The current results reveal the energetic and physiologic components of the BOLD fMRI signal and indicate the required steps towards mapping neuronal activity quantitatively by fMRI at steady-state. Consequences of these results from rat brain for similar calibrated BOLD fMRI studies in the human brain are discussed.

authors note that Fig. 1 a and c, the third and fourth panels of Fig. 3a, and the first panel of Fig. 3b were printed incorrectly due to a printer's error. The corrected figures and their legends appear below.

The blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) method, which is sensitive to vascular paramagnetic deoxyhemoglobin, is dependent on regional values of cerebral metabolic rate of oxygen utilization (CMR(O2)), blood flow (CBF), and volume (CBV). Induced changes in deoxyhemoglobin function as an endogenous contrast agent, which in turn affects the transverse relaxation rates of tissue water that can be measured by gradient-echo and spin-echo sequences in BOLD fMRI. The purpose here was to define the quantitative relation between BOLD signal change and underlying physiologic parameters. To this end, magnetic resonance imaging and spectroscopy methods were used to measure CBF, CMR(O2), CBV, and relaxation rates (with gradient-echo and spin-echo sequences) at 7 Tesla in rat sensorimotor cortex, where cerebral activity was altered pharmacologically within the autoregulatory range. The changes in tissue transverse relaxation rates were negatively and linearly correlated with changes in CBF, CMR(O2), and CBV. The multiparametric measurements revealed that CBF and CMR(O2) are the dominant physiologic parameters that modulate the BOLD fMRI signal, where the ratios of (deltaCMR(O2)/CMR(O2)/(deltaCBF/ CBF) and (deltaCBV/CBV)/(deltaCBF/CBF) were 0.86 +/- 0.02 and 0.03 +/- 0.02, respectively. The calibrated BOLD signals (spatial resolution of 48 microL) from gradient-echo and spin-echo sequences were used to predict changes in CMR(O2) using measured changes in CBF, CBV, and transverse relaxation rates. The excellent agreement between measured and predicted values for changes in CMR(O2) provides experimental support of the current theory of the BOLD phenomenon. In gradient-echo sequences, BOLD contrast is affected by reversible processes such as static inhomogeneities and slow diffusion, whereas in spin-echo sequences these effects are refocused and are mainly altered by extravascular spin diffusion. This study provides steps by which multiparametric MRI measurements can be used to obtain high-spatial resolution CMR(O2) maps.

It is generally believed that the main olfactory system processes common odors and the accessory olfactory system is specifically for pheromones. The potential for these two systems to respond simultaneously to the same stimuli has not been fully explored due to methodological limitations. Here we examine this phenomenon using high-resolution functional magnetic resonance imaging (fMRI) to reveal simultaneously the responses in the main (MOB) and accessory olfactory bulbs (AOB) to odors and pheromones. Common odorants elicited strong signals in the MOB and weak signals in the AOB. 2-Heptanone, a known mouse pheromone, elicited strong signals in both the MOB and AOB. Urine odor, a complicated mixture of pheromones and odorants, elicited significant signals in limited regions of the MOB and large regions of the AOB. The fMRI results demonstrate that both the main and the accessory olfactory systems may respond to volatile compounds but with different selectivity, suggesting a greater integration of the two olfactory pathways than traditionally believed.

Dynamic blood oxygenation level-dependent functional MRI was applied at 7 T in the rat olfactory bulb (OB) with pulsed delivery of iso-amyl acetate (IAA) and limonene. Acquisition times for singleslice and whole OB data were 8 and 32 s, respectively, with spatial resolution of 220 ؋ 220 ؋ 250 m. On an intrasubject basis, short IAA exposures of 0.6 min separated by 3.5-min intervals induced reproducible spatial activity patterns (SAPs) in the olfactory nerve layer, glomerular layer, and external plexiform layer. During long exposures (Ϸ10 min), the initially dominant dorsal SAPs declined in intensity and area, whereas in some OB regions, the initially weak ventral͞lateral SAPs increased first and then decreased. The SAPs of different concentrations were topologically similar, which implies that whereas an odor at various concentrations activates the same subsets of receptor cells, different concentrations are assessed and discriminated by variable magnitudes of laminarspecific activations. IAA and limonene reproducibly activated different subsets of receptor cells with some overlaps. Whereas qualitative topographical agreement was observed with results from other methods, the current dynamic blood oxygenation level-dependent functional MRI results can provide quantitative SAPs of the entire OB.blood oxygenation level-dependent ͉ functional mapping ͉ olfactory bulb I n mammals, olfactory behaviors such as determination of food palatability and searching require accurate assessment and discrimination of different odor types, concentrations, and exposure duration (1). Distinctions between these behavioral tasks are believed to rely on a spatial-encoding mechanism in which different odor and concentrations evoke spatial activity patterns (SAPs) in the olfactory bulb (OB). The SAPs are derived from functionally induced activity in olfactory receptor neurons that synapse at specific glomeruli (2).Insights into the coding of olfactory information have been partially inferred from SAPs in the OB, where the data can be obtained by various methods: 2-deoxyglucose autoradiography (3), electrophysiology (4), c-fos expression (5), functional MRI (fMRI) (6), and optical imaging of voltage-sensitive dyes (7) or intrinsic signals (8). Experimental limitations of each method affect data interpretations because each method maps a specific signal. Certain experimental criteria have to be met for olfactory perception to be systematically and ideally derived from the functional architecture revealed by the SAPs: (i) the neuroanatomy of the whole OB has to be mapped; (ii) the dynamic nature of SAPs in the whole OB has to be mapped with both high spatial and temporal resolutions; (iii) laminar-specific activations in the different layers have to be quantitated; and (iv) reproducibility of SAPs has to be established in a quantitative manner such that the effects of stimulus parameters (e.g., odor type, concentration, and exposure duration) can be easily identified and separated. If each criterion is met on an intrasubject basis by a par...

Magnetic resonance imaging (MRI) and spectroscopy (MRS) were used at a magnetic field strength of 7 T to measure CBF and CMRO2 in the sensorimotor cortex of mature rats at different levels of cortical activity. In rats maintained on morphine anesthesia, transitions to lower activity and higher activity states were produced by administration of pentobarbital and nicotine, respectively. Under basal conditions of morphine sulfate anesthesia, CBF was 0.75 +/- 0.09 mL x g(-1) x min(-1) and CMRO2 was 3.15 +/- 0.18 micromol x g(-1) x min(-1). Administration of sodium pentobarbital reduced CBF and CMRO2 by 66% +/- 16% and 61% +/- 6%, respectively (i.e., "deactivation"). In contrast, administration of nicotine hydrogen tartrate increased CBF and CMRO2 by 41% +/- 5% and 30% +/- 3%, respectively (i.e., "activation"). The resting values of CBF and CMRO2 for alpha-chloralose anesthetized rats were 0.40 +/- 0.09 mL x g(-1) x min(-1) and 1.51 +/- 0.06 micromol x g(-1) x min(-1), respectively. Upon forepaw stimulation, CBF and CMRO2 were focally increased by 34% +/- 10% and 26% +/- 12%, respectively, above the resting nonanesthetized values (i.e., "activation"). Incremental changes in CBF and CMRO2, when expressed as a percentage change for "deactivation" and "activation" from the respective control conditions, were linear (R2 = 0.997) over the entire range examined with the global and local perturbations. This tight correlation for cerebral oxygen delivery in vivo is supported by a recent model where the consequence of a changing effective diffusivity of the capillary bed for oxygen, D, has been hypothetically shown to be linked to alterations in CMRO2 and CBF. This assumed functional characteristic of the capillary bed can be theoretically assessed by the ratio of fractional changes in D with respect to changes in CBF, signified by omega. A value 0.81 +/- 0.23 was calculated for omega with the in vivo data presented here, which in turn corresponds to a supposition that the effective oxygen diffusivity of the capillary bed is not constant but presumably varies to meet local requirements in oxygen demand in a similar manner with both "deactivation" and "activation."

Changes in cerebral blood flow (CBF), volume (CBV), and oxygenation (blood-oxygenation level dependent (BOLD)) during functional activation are important for calculating changes in cerebral metabolic rate of oxygen consumption (CMRo 2 ) from calibrated functional MRI (fMRI). An important part of this process is the CBF/CBV relationship, which is signified by a power-law parameter: c = ln (1 + DCBV/CBV)/ln (1 + DCBF/CBF). Because of difficulty in measuring CBF and CBV with MRI, the value of c is therefore assumed to be B0.4 from a prior primate study under hypercapnia. For dynamic fMRI calibration, it is important to know if the value of c varies after stimulation onset. We measured transient relationships between DCBF, DCBV, and DBOLD by multimodal MRI with temporal resolution of 500 ms (at 7.0 T) from the rat somatosensory cortex during forepaw stimulation, where the stimulus duration ranged from 4 to 32 secs. Changes in CBF and BOLD were measured before the administration of the contrast agent for CBV measurements in the same subjects. We observed that the relationship between DCBF and DCBV varied dynamically from stimulation onset for all stimulus durations. Typically after stimulation onset and at the peak or plateau of the DCBF, the value of c ranged between 0.1 and 0.2. However, after stimulation offset, the value of c increased to 0.4 primarily because of rapid and slow decays in DCBF and DCBV, respectively. These results suggest caution in using dynamic measurements of DCBF and DBOLD required for calculating DCMRo 2 for functional stimulation, when either DCBV has not been accurately measured or a fixed value of c during hypercapnia perturbation is used.

The rat olfactory bulb contains ϳ2000 functional units called glomeruli which are used to recognize specific characteristics of odorants. Activity localization of individual glomerulae (ϳ0.002 L) has important consequences for understanding mechanisms in olfactory information encoding. High-resolution functional MRI (fMRI) data from the rat olfactory bulb are presented using the blood oxygenation level dependent (BOLD) method at 7 T. Either individual or clusters of fMRI voxels suggestive of activity in the olfactory nerve and glomerular layers were reproducibly detected with repeated 2-min exposures of iso-amyl acetate at spatial resolution of 0.001-0.003 L. The importance of glomerular clustering for olfaction and the implications of BOLD mapping with even higher spatial resolution (i.e., Ӷ0.001 L voxels) are discussed. High-resolution in vivo mapping of the rat olfactory bulb with fMRI at high magnetic field promises to provide novel data for understanding olfaction.