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Levo-tetrahydropalmatine (l-THP) has shown significant promise in preclinical and clinical studies to treat drug addiction. Pharmacological MRI methods can elucidate the regional cerebral effects of l-THP, but there are potential confounds from the use of general anesthesia. To investigate the possible anesthetic-drug interactions for the pharmacological MRI result of acute l-THP, we examined acute blood oxygen level-dependent responses of both 5 and 20 mg/kg l-THP in naive rats during general anesthesia achieved with three agents: isoflurane, medetomidine, and urethane. We found that with acute l-THP administration, isoflurane revealed the smallest blood oxygen level-dependent activation areas. In addition, urethane had the most activation areas; however, they were all negative. Medetomidine showed mixed positive and negative activations. Region-specific interactions were found between the l-THP-induced blood oxygen level-dependent responses and the anesthetic agents.

SENSE reconstruction suffers from an ill-conditioning problem, which increasingly lowers the signal-to-noise ratio (SNR) as the reduction factor increases. Ill-conditioning also degrades the convergence behavior of iterative conjugate gradient reconstructions for arbitrary trajectories. Regularization techniques are often used to alleviate the ill-conditioning problem. Based on maximum a posteriori statistical estimation with a Huber Markov random field prior, this study presents a new method for adaptive regularization using the image and noise statistics. The adaptive Huber regularization addresses the blurry edges in Tikhonov regularization and the blocky effects in total variation (TV) regularization. Phantom and in vivo experiments demonstrate improved image quality and convergence speed over both the unregularized conjugate gradient method and Tikhonov regularization method, at no increase in total computation time. Magn Reson Med 60:414 – 421, 2008. © 2008 Wiley

Contrast-to-noise ratio (CNR) in blood oxygenation level-dependent (BOLD) based functional MRI (fMRI) studies is a fundamental parameter to determine statistical significance and therefore to map functional activation in the brain. The CNR is defined here as BOLD contrast with respect to temporal fluctuation. In this study, a theoretical noise model based on oxygenation-sensitive MRI signal formation is proposed. No matter what the noise sources may be in the signal acquired by a gradient-echo echo-planar imaging pulse sequence, there are only three noise elements: apparent spin density fluctuations, S(0)(t); transverse relaxation rate fluctuations, R(2) (*)(t); and thermal noise, n(t). The noise contributions from S(0)(t), R(2) (*)(t), and n(t) to voxel time course fluctuations were evaluated as a function of echo time (TE) at 3 T. Both noise contributions caused by S(0)(t) and R(2) (*)(t) are significantly larger than that of thermal noise when TE = 30 ms. In addition, the fluctuations between S(0)(t) and R(2) (*)(t) are cross-correlated and become a noise factor that is large enough and cannot be ignored. The experimentally measured TE dependences of noise, temporal signal-to-noise ratio, and BOLD CNR in finger-tapping activation regions were consistent with the proposed model. Furthermore, the proposed theoretical models not only unified previously proposed BOLD CNR models, but also provided mechanisms for interpreting apparent controversies and limitations that exist in the literature.

The spatial relationship between a measured fMRI signal and its underlying neuronal activity remains unclear. One obstacle is the localization of neuronal activity; another is the spatial resolution of fMRI. In the present study, high-resolution BOLD and CBV fMRI experiments (voxel size: 156 x 156 x 2000 microm3) were conducted in the rat whisker barrel cortex at 3 T; neuronal activity across cortical layers was mapped using the Fos expression technique. Results show that BOLD response is weighted by blood volume and that pixels with high BOLD response can be located at the cortical surface or in deep layers, depending on local vasculature. In contrast to BOLD response, the pixels with high CBV response were consistently clustered in the deep cortical layers. Percentage-CBV change in cortical layers IV-V was 7.3 +/- 1.5%, which was significantly higher than in layers I-III (4.1 +/- 0.9%) and VI (4.3 +/- 0.7%) (mean +/- SEM). The laminar distribution of CBV response correlates well with neuronal activity localized by Fos expression. We conclude that neuronal activity can be inferred from CBV fMRI data with high spatial accuracy. The data indicate that both intracolumn functional connectivity and neurovascular coupling can be studied using CBV fMRI.

Functional magnetic resonance imaging (fMRI) was conducted to observe the effects of cocaine administration on the physiological fluctuations of fMRI signal in two brain regions. Seven long-term cocaine users with an average age of 32 years and 8 years of cocaine use history were recruited for the study. A T2*-weighted fast echo-planar imaging (EPI) pulse sequence was employed at 1.5 T to acquire three sets of brain images for each subject under three conditions (at rest, after saline injection, and after cocaine injection [0.57 mg/kg]). Cross-correlation maps were constructed using the synchronous, low frequency signal from voxel time courses after filtering respiratory, cardiac, and other physiological noise. A quantitative evaluation of the changes in functional connectivity was made using spatial correlation coefficient (SCC) analysis. A marked 50% reduction in SCC values in the region of primary visual cortex and 43% reduction in SCC values in the region of primary motor cortex were observed after cocaine administration. This significant reduction in SCC values in these cortical regions is a reflection of changes in neuronal activity. It is suggested that the observed changes in low frequency components after acute cocaine administration during a resting, no-task situation may be used as a baseline reference source when assessing the effects of cocaine on task-driven activation or on mesolimbic dopamine pathways.

Differentiation of absolute metabolite concentrations between gray and white matter in the occipital region of normal human brain was performed by in vivo localized single-voxel 1H magnetic resonance spectroscopy at 1.5 Tesla with long echo time (136 ms). With the combination of image segmentation between white and gray matter and cerebrospinal fluid, signal compensation of T1 and T2 effects, tissue water signal as the internal concentration reference, as well as compensation by different water contents in gray and white matters, it was determined that the levels of N-acetylaspartate (NAA), creatine and/or phosphocreatine (Cr), and choline-containing compounds (Cho) in gray matter were significantly higher than in white matter. The averaged NAA, Cr, and Cho concentrations in gray matter were 11.0, 9.7, and 1.9 mM/liter, respectively, in comparison with 7.5, 5.2, and 1.6 mM/liter in white matter. These results suggest that precise composition of white and gray matter and cerebrospinal fluid is necessary to avoid partial voluming effect in a single voxel and to accurately quantify the metabolite concentrations.

In resting-state functional MRI studies, the global signal (operationally defined as the global average of resting-state functional MRI time courses) is often considered a nuisance effect and commonly removed in preprocessing. This global signal regression method can introduce artifacts, such as false anticorrelated resting-state networks in functional connectivity analyses. Therefore, the efficacy of this technique as a correction tool remains questionable. In this article, we establish that the accuracy of the estimated global signal is determined by the level of global noise (i.e., non-neural noise that has a global effect on the resting-state functional MRI signal). When the global noise level is low, the global signal resembles the resting-state functional MRI time courses of the largest cluster, but not those of the global noise. Using real data, we demonstrate that the global signal is strongly correlated with the default mode network components and has biological significance. These results call into question whether or not global signal regression should be applied. We introduce a method to quantify global noise levels. We show that a criteria for global signal regression can be found based on the method. By using the criteria, one can determine whether to include or exclude the global signal regression in minimizing errors in functional connectivity measures.

The absolute metabolite quantification method of Thulborn and Ackerman [J. Magn. Reson 55, 357 (1983)] in which the tissue water proton signal is used as an internal intensity standard and its more recent variation in which NMR peak intensities are referenced to that of the natural abundance deuterium signal of water [Li et al., SMRM Abstr.2, 825 (1988); Song et al, Magn. Reson. Med.25, 45 (1992) have been implemented to obtain absolute phosphate metabolite concentrations in subcutaneous RIF-1 tumors during untreated growth and following treatment with 5-fluorouracil. The equivalence of these two hydrogen isotopes as intensity standards and the validity of their use in the determination of absolute metabolite concentrations in vivo by NMR has been demonstrated. On matched in vivo and extract tumor samples (n = 5), excellent agreement has been obtained between nucleoside triphosphate concentrations determined by NMR and those derived by HPLC analysis for the control tumors. Following 3 days of untreated growth, absolute concentrations of phosphate metabolites in RIF-1 tumors (n = 10) decreased significantly, except for the Pi concentration which did not vary. For the treated tumors (n = 10) there were no changes in metabolite concentrations except for a decrease in the PCr and, possibly, Pi concentrations. The PCr/Pi ratio in the latter tumors did not change. These observations suggest that changes in absolute metabolite concentrations may be more sensitive indices of response to therapy than changes in metabolite peak amplitude ratios, a parameter commonly used to express in vivo NMR data.© 1992 Academic Press,Inc.

An inversion-recovery pulse sequence and solenoidal surface coil were employed to determine the spin-lattice relaxation time (T1) in murine tumors (RIF-1 and SCCVII). Reduction in T1s of inorganic phosphate (Pi) and nucleotide triphosphates (NTP) has been observed in irradiated tumors compared with unirradiated tumors. The reduction is accompanied by tumor regression and improved tumor energetic status in both tumor lines. The results of the T1 measurement of phosphate metabolites in tumors suggest that partial saturation effects may exist in spectra and could effect quantitative analysis when short repetition time is used. The reduction in T1s of Pi and NTP may be attributed to the active biochemical exchange and better tumor oxygenation in irradiated tumors.

Recent developments in functional MRI (fMRI) technology with high spatial and temporal resolution have made it possible to noninvasively detect spontaneous low-frequency oscillations (SLOs) and quantify their functional synchrony in the human brain. In the present fMRI study the dynamic characteristics of the functional synchrony between SLOs were quantitatively determined by the phase shift index (PSI). With the use of an fMRI-guided voxel-selection method, the SLOs and their functional synchrony were found to be modulated by different memory tasks. The results demonstrate that SLOs in episodic memory-related circuitry have significantly higher synchrony during the performance of declarative memory-encoding activities compared to nondeclarative memory-encoding activities. It is suggested that the dynamic property of SLOs and the quantitative assessment of their functional synchrony could be utilized as a biomarker to noninvasively characterize localized pathophysiological functions in the human brain.

Sensitivity-encoded spectroscopic imaging (SENSE-SI) reduces scanning time by using multiple coils for parallel signal acquisition. Significant artifacts could be induced by SENSE-SI, mainly due to the low-resolution nature of spectroscopic imaging. The present study introduces a novel method to reduce the artifacts. High-resolution sensitivity maps are used in low-resolution SENSE reconstruction. An intermediate unaliased image is obtained after SENSE reconstruction. Based on the intermediate image, the sensitivity maps are optimized and then the SENSE reconstruction is performed again. The final unaliased image has significantly reduced artifacts.

Functional MRI (fMRI) was employed to determine whether repeated heroin self-administration (SA) produces tolerance or sensitization in the brain of heroin-SA rats. Twelve rats were evenly divided into saline and heroin (0.06 mg/kg, 4 hr/day) SA groups. There was a progressive increase in drug-SA behavior and daily heroin intake during the 8-9 days of heroin-SA training. Within 24 hr after the last session of daily SA, acute heroin (0.1 mg/kg) administration induced regional blood oxygen level-dependent (BOLD) signals in both groups of rats. The positive BOLD signals appeared mainly in the cortical regions, including the prefrontal cortex, cingulate, and olfactory cortex, while the negative BOLD signals were predominantly located in subcortical regions such as caudate and putamen, nucleus accumbens, thalamus, and hypothalamus. However, the number of activated voxels or BOLD-signal intensity was significantly less in heroin-SA rat in regions of prefrontal cortex, nucleus accumbens, and thalamus, etc., compared to the changes in the saline control rats. Application of gamma-vinyl GABA (100 mg/kg), an irreversible GABA-transaminase inhibitor, failed to block opiate actions in the heroin-SA rats. Together, these data suggest that repeated heroin-SA produces tolerance or desensitization of opiate actions in the rat brain, which may in turn potentiate drug SA behavior and drug intake.

MRI gradient coil design is a type of nonlinear constrained optimization. A practical problem in transverse gradient coil design using the conjugate gradient descent (CGD) method is that wire elements move at different rates along orthogonal directions (r, ,z ), and tend to cross, breaking the constraints. A momentum-weighted conjugate gradient descent (MW-CGD) method is presented to overcome this problem. This method takes advantage of the efficiency of the CGD method combined with momentum weighting, which is also an intrinsic property of the Levenberg-Marquardt algorithm, to adjust step sizes along the three orthogonal directions. A water-cooled, 12.8 cm inner diameter, three axis torque-balanced gradient coil for rat imaging was developed based on this method, with an efficiency of 2.13, 2.08, and 4.12 mT m -1 A -1 along X, Y, and Z, respectively. Experimental data demonstrate that this method can improve efficiency by 40% and field uniformity by 27%. This method has also been applied to the design of a gradient coil for the human brain, employing remote current return paths. The benefits of this design include improved gradient field uniformity and efficiency, with a shorter length than gradient coil designs using coaxial return paths. Magn Reson Med 51:158 –164, 2004.

A total of 45 male Sprague-Dawley rats were employed to determine whether cocaine or cocaine methiodide (CM) administration can induce a significant increase in mean arterial blood pressure (MABP) in rats, and whether such an increase in MABP can produce a global increase in blood oxygenation level-dependent (BOLD) contrast in the rat brain detectable by functional magnetic resonance imaging (fMRI). Cocaine methiodide is a quaternary derivative of cocaine that shares the same cardiovascular effects of cocaine, but does not penetrate the blood-brain barrier (BBB). Experimental results demonstrated that both CM (with doses of 2.5 and 7.5 mg/kg) and cocaine (with doses of 1.25 and 5.0 mg/kg) can induce a significant MABP change (30-80%). It was found that CM can only produce scattered, weak, and transient BOLD signals in a few voxels of the rat brain, and that these MABP-induced BOLD signals are not dose-dependent. In contrast, the administration of cocaine induced dose-dependent biphasic BOLD signals that were consistent with pharmacologically-induced cerebral vascular constriction and neuronal activity in the mesolimbic systems of the rat brain. The potential confounding factor of the MABP changes had little effect on the interpretation of drug-induced BOLD signal changes. These results confirm that the BOLD-weighted fMRI method can be extended to map drug-induced neuronal activity.

The transient relationship between arterial cerebral blood flow (CBF(A)) and total cerebral blood volume (CBV(T)) was determined in the rat brain. Five rats anesthetized with urethane (1.2 g/kg) were examined under graded hypercapnia conditions (7.5% and 10% CO(2) ventilation). The blood oxygenation level-dependent (BOLD) contrast was determined by a gradient-echo echo-planar imaging (GE-EPI) pulse sequence, and CBV(T) changes were determined after injection of a monocrystalline iron oxide nanocolloid (MION) contrast agent using an iron dose of 12 mg/kg. The relationship between CBV(T) and CBF(A) under transient conditions is similar to the power law under steady-state conditions. In addition, the transient relationship between CBV(T) and CBF(A) is region-specific. Voxels with > or =15% BOLD signal changes from hypercapnia (7.5% CO(2) ventilation) have a larger power index (alpha = 3.26), a larger maximum possible BOLD response (M = 0.85), and shorter T(*)(2) (32 ms) caused by deoxyhemoglobin, compared to voxels with

A MultiEcho Segmented EPI with z-shimmed BAckground gradient Compensation (MESBAC) pulse sequence is proposed and validated for functional MRI (fMRI) study in regions suffering from severe susceptibility artifacts. This sequence provides an effective tradeoff between spatial and temporal resolution and reduces image distortion and signal dropout. The blood oxygenation level-dependent (BOLD)-weighted fMRI signal can be reliably obtained in the region of the orbitofrontal cortex (OFC). To overcome physiological motion artifacts during prolonged multisegment EPI acquisition, two sets of navigator echoes were acquired in both the readout and phase-encoding directions. Ghost artifacts generally produced by single-shot EPI acquisition were eliminated by separately placing the even and odd echoes in different k-space trajectories. Unlike most z-shim methods that focus on increasing temporal resolution for event-related functional brain mapping, the MESBAC sequence simultaneously addresses problems of image distortion and signal dropout while maintaining sufficient temporal resolution. The MESBAC sequence will be particularly useful for pharmacological and affective fMRI studies in brain regions such as the OFC, nucleus accumbens, amygdala, parahippocampus, etc.

Midfield proton magnetic resonance spectroscopy (MRS) provides a noninvasive method to monitor glutamate and glutamine (Glx) levels in vivo. Experiments to detect the gamma and beta resonances of Glx have been performed by using commercial 0.5 T and 1.5 T MR scanners on seven patients with elevated blood ammonia and eight normal volunteers. Compared with the spectral sensitivity obtained on an otherwise identical system operating at 1.5 T, the singlet resonance of N-acetyl aspartate (NAA) was decreased by a factor of 1.48, which is significantly less than expected using the ratio of Boltzman populations at the two field strengths. However, the resonances of Glx at 0.5 T increased in signal-to-noise ratio (SNR) by a factor of 2. The increased SNR of Glx is principally due to improved B0 main-field homogeneity and collapse of the strongly J-coupled Glx resonances. Our preliminary results suggest that midfield proton MRS will provide significant clinical utility in the detection of Glx levels in human brain.

Treatment of RIF-1 solid tumors with 5-fluorouracil (5-FU, 100 or 200 mg/kg, ip) caused substantial regression of the tumors, with regrowth initiated on Day 6 (100 mg/kg) or Day 9 (200 mg/kg). Blood perfusion in the tumor, estimated by uptake of 86Rb+, was significantly increased after treatment with 5-FU, while Rb+ uptake in normal tissues (skin, muscle) was unaffected. The increase in tumor perfusion during the first few days following treatment was significantly greater in animals treated with the higher dose of 5-FU. Perfusion-dependent 86Rb+ uptake returned to control levels by the 9th day after treatment with 100 mg/kg of 5-FU, but remained elevated on Days 9-12 after the higher dose. By the 1st day following treatment with 5-FU, in vivo 31P NMR spectra of treated tumors indicated significantly higher ratios of phosphocreatine to Pi, higher pH, and lower ratios of Pi to nucleoside triphosphates compared to untreated age-matched controls. These changes persisted for 9 days following the lower 5-FU dose and for at least 12 days following the higher dose. Treatment with 5-FU induces profound, dose-dependent changes in tumor bioenergetics, which may result, at least in part, from changes in tumor perfusion after cytoreduction.