We report that visual stimulation produces an easily detectable (5-20%) transient increase in the intensity of water proton magnetic resonance signals in human primary visual cortex in gradient echo images at 4-T magnetic-field strength. The observed changes predominantly occur in areas containing gray matter and can be used to produce highspatial-resolution functional brain maps in humans. Reducing the image-acquisition echo time from 40 msec to 8 msec reduces the amplitude of the fractional signal change, suggesting that it is produced by a change in apparent transverse relaxation time T2. The amplitude, sign, and echo-time dependence of these intrinsic signal changes are consistent with the idea that neural activation increases regional cerebral blood flow and concomitantly increases venous-blood oxygenation.Magnetic-resonance imaging (MRI) of rodent brains at high (7-T) magnetic-field strength shows proton signal-intensity alterations related to blood oxygenation in regions close to local blood vessels (1-3). We have termed this phenomenon blood oxygenation-level-dependent (BOLD) contrast and have demonstrated that the underlying mechanism is a magnetic-susceptibility variation caused by deoxyhemoglobin, an endogenous paramagnetic contrast agent. It was further demonstrated that this magnetic-susceptibility effect could be used to measure in vivo changes in hemodynamics. For example, pharmacologically induced changes in cerebral blood flow and oxygen utilization produce measurable changes in BOLD contrast in the rat cerebral cortex. Similar results have recently been demonstrated in cat brain (4).There is increased evidence that a local elevation in human-brain venous-blood oxygenation accompanies an increase in neuronal activity (5-8). For example, positron emission tomography imaging experiments demonstrate stimulation-produced increases in regional cerebral blood flow without significantly changing local oxygen use, thus predicting an elevation in venous-blood oxygenation (6, 7). This result suggested that BOLD contrast imaging could be used to map human mental operations. To examine whether detectable intrinsic magnetic-susceptibility changes are produced in the human brain in response to neuronal activation, we studied the effect of visual stimulation on gradient echo images of human visual cortex acquired at high-magneticfield strength. In general, high-field strength increases the magnitude of susceptibility contrast effects, accentuating BOLD contrast. MATERIALS AND METHODSMRI experiments were done with a 4-T whole-body imaging system with actively shielded gradient coils [Sisco (Sunnyvale, CA)/Siemens (Erlangen, F.R.G.)]. Approval for these human experiments was obtained from the institutional review board of the University of Minnesota Medical School. Radiofrequency power deposition was kept two orders of magnitude below Food and Drug Administration specificabsorption rate guidelines. A snugly fitted head holder with a curved-surface radiofrequency coil (14 cm in diameter) was used to limit...

Relative cerebral blood flow changes can be measured by a novel simple blood flow measurement technique with endogenous water protons as a tracer based on flow-sensitive alternating inversion recovery (FAIR). Two inversion recovery (IR) images are acquired by interleaving slice-selective inversion and nonselective inversion. During the inversion delay time after slice-selective inversion, fully magnetized blood spins move into the imaging slice and exchange with tissue water. The signal enhancement (FAIR image) measured by the signal difference between two images is directly related to blood flow. For functional MR imaging studies, two IR images are alternatively and repeatedly acquired during control and task periods. Relative signal changes in the FAIR images during the task periods represent the relative regional cerebral blood flow changes. The FAIR technique has been successfully applied to functional brain mapping studies in humans during finger opposition movements. The technique is capable of generating microvascular-based functional maps.

The amide proton transfer (APT) effect has emerged as a unique endogenous molecular imaging contrast mechanism with great clinical potentials. However, in vivo quantitative mapping of APT using the conventional asymmetry analysis is difficult due to the confounding Nuclear Overhauser Effect (NOE) and the asymmetry of the magnetization transfer (MT) effect. Here we showed that the asymmetry of MT contrast from immobile macromolecules is highly significant, and the wide spectral separation associated with a high magnetic field of 9.4 T delineates APT and NOE peaks in a Z-spectrum. Therefore, high resolution apparent APT and NOE maps can be obtained from measurements at three offsets. The apparent APT value was greater in gray matter compared to white matter in normal rat brain, and was sensitive to tissue acidosis and correlated well with ADC in the rat focal ischemic brain. In contrast, no ischemia-induced contrast was observed in the apparent NOE map. The concentration-dependence and the pH insensitivity of NOE were confirmed in phantom experiments. Our results demonstrate that in vivo apparent APT and NOE maps can be easily obtained at high magnetic fields, and the pH-insensitive NOE may be a useful indicator of mobile macromolecular contents.

After its discovery in 1990, blood oxygenation level-dependent (BOLD) contrast in functional magnetic resonance imaging (fMRI) has been widely used to map brain activation in humans and animals. Since fMRI relies on signal changes induced by neural activity, its signal source can be complex and is also dependent on imaging parameters and techniques. In this review, we identify and describe the origins of BOLD fMRI signals, including the topics of (1) effects of spin density, volume fraction, inflow, perfusion, and susceptibility as potential contributors to BOLD fMRI, (2) intravascular and extravascular contributions to conventional gradient-echo and spin-echo BOLD fMRI, (3) spatial specificity of hemodynamic-based fMRI related to vascular architecture and intrinsic hemodynamic responses, (4) BOLD signal contributions from functional changes in cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of O(2) utilization (CMRO(2)), (5) dynamic responses of BOLD, CBF, CMRO(2), and arterial and venous CBV, (6) potential sources of initial BOLD dips, poststimulus BOLD undershoots, and prolonged negative BOLD fMRI signals, (7) dependence of stimulus-evoked BOLD signals on baseline physiology, and (8) basis of resting-state BOLD fluctuations. These discussions are highly relevant to interpreting BOLD fMRI signals as physiological means.

Chemical exchange saturation transfer (CEST) and spin-locking (SL) experiments were both able to probe the exchange process between protons of nonequivalent chemical environments. To compare the characteristics of the CEST and SL approaches in the study of chemical exchange effects, we performed CEST and SL experiments at varied pH and concentrated metabolite phantoms with exchangeable amide, amine, and hydroxyl protons at 9.4 T. Our results show that: (i) on-resonance SL is most sensitive to chemical exchanges in the intermediate-exchange regime and is able to detect hydroxyl and amine protons on a millimolar concentration scale. Off-resonance SL and CEST approaches are sensitive to slow-exchanging protons when an optimal SL or saturation pulse power matches the exchanging rate, respectively. Recently, there has been an increasing number of in vivo studies that have used the chemical exchange (CE) effect to probe the tissue microenvironment and provide novel imaging contrasts that are not available from conventional MRI techniques. Most of these studies adopted either a chemical exchange saturation transfer (CEST) or a spinlocking (SL) approach to detect contrast in tissue pH or the population of labile protons, which have a Larmor frequency different from water. Ideally, a CE-sensitive imaging contrast should have good sensitivity and vary monotonically with pH and linearly with labile proton concentration. The CE contrast is determined by many parameters, such as the exchange rate between water and labile protons (k ex ), the difference in their Larmor frequencies (d), the populations of the exchangeable protons, water T 1 , and the magnetic field strength (B 0 ). The CE effect in MRI is also highly sensitive to a ratio of k ex to d. k ex /d, which indicates the CE kinetics, is usually divided into three regimes: slow (k ex /d ( 1), intermediate (k ex /d $ 1), and fast exchange (k ex /d ) 1). CEST techniques are mostly applied at the slow-or slow-to intermediate-exchange regime (1,2), whilereas the CE is often assumed to occur at the fast-exchange regime for SL applications (3,4).In CEST studies that are based upon endogenous contrast, selective off-resonance irradiation of labile protons of protein or peptide side chains attenuates the water signal via exchange between these labile protons and bulk water. The signal intensity as a function of irradiation frequency, often referred to as the Z-spectrum, can be expressed by the magnetization transfer ratio (MTR):where V is the frequency offset with respect to water. In practice, the conventional non-CE magnetization transfer effect and direct water saturation (or the so-called spillover effect) also affect the Z-spectrum, and these effects are assumed to be symmetrical around the water resonance frequency. To minimize these non-CE contributions, CEST contrast in MRI is usually extracted from two images-one acquired with off-resonance irradiation on the targeted labile proton and the other as a control with opposite offset frequency from the water (5). The norma...